Elucidating the Signaling Pathways Involved in Erectile Dysfunction

Ecem      Kaya-Sezginer; Aybuke      Celik; Omer   Faruk   Kirlangic
doi:10.2174/0115743624302323240522101746
Abstract

Background: Erectile Dysfunction (ED) is a common sexual disorder among men aged 20 years and over. It is predominantly characterized by alterations in the key physiological pathways regulating erectile function, such as nitric oxide and Ras homolog gene family member A (RhoA)/Rho-associated protein kinase (ROCK). Beyond these pathways, multiple molecular signaling networks are involved in ED pathogenesis.
Objective: This review aims to describe the major signal transduction pathways that impact erectile function and contribute to the introduction of the pathogenesis of ED.
Methods: A literature review of ED was performed from 2000 to 2023 using PubMed, Scopus, and Embase. “ED” and “related signaling pathway”, “molecular mechanisms” terms were used.
Results: Further basic and clinical studies are required to define the underlying molecular mechanisms of ED. The signaling pathways that were not affected by phosphodiesterase type 5 inhibitors (PDE5i) may be the reason for the reduced efficacy of this first-line treatment option in a variety of conditions.
Conclusion: There is still a need for a deeper description of the molecular mechanisms in terms of fibrosis, angiogenesis, apoptosis, inflammation, oxidative stress, autophagy, and hypoxia to identify new possible targets underlying the pathogenesis of ED. This comprehensive review expounds on the principal signaling pathways, offering valuable insights that may catalyze the development of innovative and enhanced therapies for managing ED.
Graphical Abstract

[1]
Niu Y, Lin G, Pan J, et al. Deciphering the myth of icariin and synthetic derivatives in improving erectile function from a molecular biology perspective: A narrative review. Transl Androl Urol  2022; 11(7): 1007-22.
 [http://dx.doi.org/10.21037/tau-22-232] [PMID: 35958901]

[2]
Guay AT. ED2: Erectile dysfunction = endothelial dysfunction. Endocrinol Metab Clin North Am  2007; 36(2): 453-63.
 [http://dx.doi.org/10.1016/j.ecl.2007.03.007] [PMID: 17543729]

[3]
Andersson KE. Erectile physiological and pathophysiological pathways involved in erectile dysfunction. J Urol  2003; 170(2S): S6-S13.
 [http://dx.doi.org/10.1097/01.ju.0000075362.08363.a4] [PMID: 12853766]

[4]
Heiss E, Dirsch V. Regulation of eNOS enzyme activity by posttranslational modification. Curr Pharm Des  2014; 20(22): 3503-13.
 [http://dx.doi.org/10.2174/13816128113196660745] [PMID: 24180389]

[5]
Wu J, Huang Y, Zhang J, Xiang Z, Yang J. LncRNA CPhar mediates exercise-induced cardioprotection by promoting eNOS phosphorylation at Ser1177 via DDX17/PI3K/Akt pathway after MI/RI. Int J Cardiol  2022; 350: 16.
 [http://dx.doi.org/10.1016/j.ijcard.2021.12.040] [PMID: 34954278]

[6]
Lee JH, Parveen A, Do MH, Lim Y, Shim SH, Kim SY. Lespedeza cuneata protects the endothelial dysfunction via eNOS phosphorylation of PI3K/Akt signaling pathway in HUVECs. Phytomedicine  2018; 48: 1-9.
 [http://dx.doi.org/10.1016/j.phymed.2018.05.005] [PMID: 30195866]

[7]
Jin LM. Angiotensin II signaling and its implication in erectile dysfunction. J Sex Med  2009; 6 (Suppl. 3): 302-10.
 [http://dx.doi.org/10.1111/j.1743-6109.2008.01188.x] [PMID: 19267853]

[8]
Hatzimouratidis K, Salonia A, Adaikan G, et al. Pharmacotherapy for Erectile Dysfunction: Recommendations from the fourth International Consultation for Sexual Medicine (ICSM 2015). J Sex Med  2016; 13(4): 465-88.
 [http://dx.doi.org/10.1016/j.jsxm.2016.01.016] [PMID: 27045254]

[9]
Zhang X, Zhao F, Zhao JF, Fu HY, Huang XJ, Lv BD. PDGF-mediated PI3K/AKT/β-catenin signaling regulates gap junctions in corpus cavernosum smooth muscle cells. Exp Cell Res  2018; 362(2): 252-9.
 [http://dx.doi.org/10.1016/j.yexcr.2017.11.025] [PMID: 29174980]

[10]
Lu J, Xin Z, Zhang Q, et al. Beneficial effect of PEDF-transfected ADSCs on erectile dysfunction in a streptozotocin-diabetic rat model. Cell Tissue Res  2016; 366(3): 623-37.
 [http://dx.doi.org/10.1007/s00441-016-2494-7] [PMID: 27655233]

[11]
Hui J, Liu R, Zhang H, He S, Wei A. Screening and identification of critical biomarkers in erectile dysfunction: Evidence from bioinformatic analysis. PeerJ  2020; 8: e8653.
 [http://dx.doi.org/10.7717/peerj.8653] [PMID: 32161689]

[12]
Heaton JPW, Varrin SJ, Morales A. The characterization of a bio-assay of erectile function in a rat model. J Urol  1991; 145(5): 1099-102.
 [http://dx.doi.org/10.1016/S0022-5347(17)38543-9] [PMID: 2016801]

[13]
Yin GN, Choi MJ, Kim WJ, et al. Inhibition of Ninjurin 1 restores erectile function through dual angiogenic and neurotrophic effects in the diabetic mouse. Proc Natl Acad Sci USA  2014; 111(26): E2731-40.
 [http://dx.doi.org/10.1073/pnas.1403471111] [PMID: 24979788]

[14]
Watabe T, Nishihara A, Mishima K, et al. TGF-β receptor kinase inhibitor enhances growth and integrity of embryonic stem cell–derived endothelial cells. J Cell Biol  2003; 163(6): 1303-11.
 [http://dx.doi.org/10.1083/jcb.200305147] [PMID: 14676305]

[15]
Hyman KM, Seghezzi G, Pintucci G, et al. Transforming growth factor–β1 induces apoptosis in vascular endothelial cells by activation of mitogen-activated protein kinase. Surgery  2002; 132(2): 173-9.
 [http://dx.doi.org/10.1067/msy.2002.125304] [PMID: 12219008]

[16]
Cabrini MR, Sezen SF, Lagoda G. Fibrotic protein expression profiles in penile tissue of patients with erectile dysfunction. Urology  2013; 82(4): 975.
 [http://dx.doi.org/10.1016/j.urology.2013.06.042]

[17]
Shin TY, Ryu JK, Jin HR, et al. Increased cavernous expression of transforming growth factor-β1 and activation of the Smad signaling pathway affects erectile dysfunction in men with spinal cord injury. J Sex Med  2011; 8(5): 1454-62.
 [http://dx.doi.org/10.1111/j.1743-6109.2010.02049.x] [PMID: 20946170]

[18]
Leungwattanakij S, Bivalacqua TJ, Usta MF, et al. Cavernous neurotomy causes hypoxia and fibrosis in rat corpus cavernosum. J Androl  2003; 24(2): 239-45.
 [http://dx.doi.org/10.1002/j.1939-4640.2003.tb02668.x] [PMID: 12634311]

[19]
Hu WL, Hu LQ, Li SW, Zheng XM, Tian BC. Expression of transforming growth factor‐β1 in penile tissue from rats with bilateral cavernosal nerve ablation. BJU Int  2004; 94(3): 424-8.
 [http://dx.doi.org/10.1111/j.1464-410X.2004.04969.x] [PMID: 15291880]

[20]
Canguven O, Lagoda G, Sezen SF, Burnett AL. Losartan preserves erectile function after bilateral cavernous nerve injury via antifibrotic mechanisms in male rats. J Urol  2009; 181(6): 2816-22.
 [http://dx.doi.org/10.1016/j.juro.2009.01.097] [PMID: 19375729]

[21]
Qabazard B, Yousif M, Mousa A, Phillips OA. GYY4137 attenuates functional impairment of corpus cavernosum and reduces fibrosis in rats with STZ-induced diabetes by inhibiting the TGF-β1/Smad/CTGF pathway. Biomed Pharmacother  2021; 138: 111486.
 [http://dx.doi.org/10.1016/j.biopha.2021.111486] [PMID: 34311523]

[22]
Shim JS, Kim DH, Bae JH, Moon DG. Effects of Omega-3 Fatty Acids on Erectile Dysfunction in a Rat Model of Atherosclerosis-induced Chronic Pelvic Ischemia. J Korean Med Sci  2016; 31(4): 585-9.
 [http://dx.doi.org/10.3346/jkms.2016.31.4.585] [PMID: 27051243]

[23]
Kim JH, Shim JS, Kim JW, et al. Molecular and Histologic evidence of novel erectile dysfunction rat model as an aging atherosclerosis model: A preliminary study. World J Mens Health  2020; 38(3): 345-52.
 [http://dx.doi.org/10.5534/wjmh.190031] [PMID: 31385467]

[24]
Chen Z, Li G, Lin H, Jiang J, Jiang R. Low androgen status inhibits erectile function by increasing pyroptosis in rat corpus cavernosum. Andrology  2021; 9(4): 1264-74.
 [http://dx.doi.org/10.1111/andr.12995] [PMID: 33657666]

[25]
Jin HR, Chung YG, Kim WJ, et al. A mouse model of cavernous nerve injury-induced erectile dysfunction: Functional and morphological characterization of the corpus cavernosum. J Sex Med  2010; 7(10): 3351-64.
 [http://dx.doi.org/10.1111/j.1743-6109.2010.01942.x] [PMID: 20646178]

[26]
Zhou F, Li GY, Gao ZZ, et al. The TGF-β1/Smad/CTGF pathway and corpus cavernosum fibrous-muscular alterations in rats with streptozotocin-induced diabetes. J Androl  2012; 33(4): 651-9.
 [http://dx.doi.org/10.2164/jandrol.111.014456] [PMID: 22016353]

[27]
Akingba AG, Burnett AL. Endothelial nitric oxide synthase protein expression, localization, and activity in the penis of the alloxan-induced diabetic rat. Mol Urol  2001; 5(4): 189-97.
 [http://dx.doi.org/10.1089/10915360152745885] [PMID: 11790282]

[28]
Zhang LW, Piao S, Choi MJ, et al. Role of increased penile expression of transforming growth factor-beta1 and activation of the Smad signaling pathway in erectile dysfunction in streptozotocin-induced diabetic rats. J Sex Med  2008; 5(10): 2318-29.
 [http://dx.doi.org/10.1111/j.1743-6109.2008.00977.x] [PMID: 18778311]

[29]
Liu T, Xin H, Li WR, et al. Effects of icariin on improving erectile function in streptozotocin-induced diabetic rats. J Sex Med  2011; 8(10): 2761-72.
 [http://dx.doi.org/10.1111/j.1743-6109.2011.02421.x] [PMID: 21967314]

[30]
Zhou F, Xin H, Liu T, et al. Effects of icariside II on improving erectile function in rats with streptozotocin-induced diabetes. J Androl  2012; 33(5): 832-44.
 [http://dx.doi.org/10.2164/jandrol.111.015172] [PMID: 22403279]

[31]
Zhang XM, Shi PH, Cao SH, Yu HJ, Azad J, Ling SC. Expression changes of transforming growth factor-beta1 and thrombospondin-1 in cavernous tissues of diabetic rats. Urol Int  2010; 84(2): 221-5.
 [http://dx.doi.org/10.1159/000277602] [PMID: 20215829]

[32]
Chen Y, Zhou B, Yu Z, et al. Baicalein alleviates erectile dysfunction associated with streptozotocin-induced Type I Diabetes by ameliorating endothelial nitric oxide synthase dysfunction, inhibiting oxidative stress and fibrosis. J Sex Med  2020; 17(8): 1434-47.
 [http://dx.doi.org/10.1016/j.jsxm.2020.04.390] [PMID: 32586748]

[33]
Li H, Xu W, Liu X, et al. JAK2 deficiency improves erectile function in diabetic mice through attenuation of oxidative stress, apoptosis, and fibrosis. Andrology  2021; 9(5): 1662-71.
 [http://dx.doi.org/10.1111/andr.13061] [PMID: 34085398]

[34]
Kwon MH, Park SH, Song KM, et al. Penile erection induces angiogenic, survival, and antifibrotic signals: Molecular events associated with penile erection induced by cavernous nerve stimulation in mice. Int J Urol  2016; 23(7): 614-22.
 [http://dx.doi.org/10.1111/iju.13105] [PMID: 27109455]

[35]
Lin CS, Ho HC, Chen KC, Lin G, Nunes L, Lue TF. Intracavernosal injection of vascular endothelial growth factor induces nitric oxide synthase isoforms. BJU Int  2002; 89(9): 955-60.
 [http://dx.doi.org/10.1046/j.1464-410X.2002.02792.x] [PMID: 12010247]

[36]
Rajasekaran M, Kasyan A, Jain A, Kim SW, Monga M. Altered growth factor expression in the aging penis: The Brown-Norway rat model. J Androl  2002; 23(3): 393-9.
 [http://dx.doi.org/10.1002/j.1939-4640.2002.tb02246.x] [PMID: 12002441]

[37]
Tomada N, Tomada I, Cruz F, Vendeira P, Neves D. Characterization of VEGF and angiopoietins expression in human corpus cavernosum during aging. J Sex Med  2010; 7(4_Part_1): 1410-8.
 [http://dx.doi.org/10.1111/j.1743-6109.2009.01648.x] [PMID: 20059658]

[38]
Neves D, Santos J, Tomada N, Almeida H, Vendeira P. Aging and orchidectomy modulate expression of VEGF receptors (Flt-1 and Flk-1) on corpus cavernosum of the rat. Ann N Y Acad Sci  2006; 1067(1): 164-72.
 [http://dx.doi.org/10.1196/annals.1354.020] [PMID: 16803982]

[39]
Musicki B, Kramer MF, Becker RE, Burnett AL. Age-related changes in phosphorylation of endothelial nitric oxide synthase in the rat penis. J Sex Med  2005; 2(3): 347-57.
 [http://dx.doi.org/10.1111/j.1743-6109.2005.20349.x] [PMID: 16422866]

[40]
Musicki B, Palese MA, Crone JK, Burnett AL. Phosphorylated endothelial nitric oxide synthase mediates vascular endothelial growth factor-induced penile erection. Biol Reprod  2004; 70(2): 282-9.
 [http://dx.doi.org/10.1095/biolreprod.103.021113] [PMID: 14522830]

[41]
Wang J, Gong X, Deng S, et al. Effect of asthma on erectile dysfunction in Rats as determined by biological network analysis. Med Sci Monit  2020; 26: e927491.
 [http://dx.doi.org/10.12659/MSM.927491] [PMID: 33341820]

[42]
Yamanaka M, Shirai M, Shiina H, et al. Vascular endothelial growth factor restores erectile function through inhibition of apoptosis in diabetic rat penile crura. J Urol  2005; 173(1): 318-23.
 [http://dx.doi.org/10.1097/01.ju.0000141586.46822.44] [PMID: 15592104]

[43]
Rogers RS, Graziottin TM, Lin C-S, Kan YW, Lue TF. Intracavernosal vascular endothelial growth factor (VEGF) injection and adeno-associated virus-mediated VEGF gene therapy prevent and reverse venogenic erectile dysfunction in rats. Int J Impot Res  2003; 15(1): 26-37.
 [http://dx.doi.org/10.1038/sj.ijir.3900943] [PMID: 12605238]

[44]
Byrne RR, Henry GD, Rao DS, et al. Vascular endothelial growth factor restores corporeal smooth muscle function in vitro. J Urol  2001; 165(4): 1310-5.
 [http://dx.doi.org/10.1016/S0022-5347(01)69890-2] [PMID: 11257707]

[45]
Henry GD, Byrne R, Hunyh TTT, et al. Intracavernosal injections of vascular endothelial growth factor protects endothelial dependent corpora cavernosal smooth muscle relaxation in the hypercholesterolemic rabbit: A preliminary study. Int J Impot Res  2000; 12(6): 334-9.
 [http://dx.doi.org/10.1038/sj.ijir.3900621] [PMID: 11416837]

[46]
Gholami SS, Rogers R, Chang J, et al. The effect of vascular endothelial growth factor and adeno-associated virus mediated brain derived neurotrophic factor on neurogenic and vasculogenic erectile dysfunction induced by hyperlipidemia. J Urol  2003; 169(4): 1577-81.
 [http://dx.doi.org/10.1097/01.ju.0000055120.73261.76] [PMID: 12629419]

[47]
Zhu GQ, Jeon SH, Bae WJ, et al. Efficient promotion of autophagy and angiogenesis using mesenchymal stem cell therapy enhanced by the low-energy shock waves in the treatment of erectile dysfunction. Stem Cells Int  2018; 2018: 1-14.
 [http://dx.doi.org/10.1155/2018/1302672] [PMID: 30228820]

[48]
Jesmin S, Sakuma I, Salah-Eldin A, Nonomura K, Hattori Y, Kitabatake A. Diminished penile expression of vascular endothelial growth factor and its receptors at the insulin-resistant stage of a type II diabetic rat model: A possible cause for erectile dysfunction in diabetes. J Mol Endocrinol  2003; 31(3): 401-18.
 [http://dx.doi.org/10.1677/jme.0.0310401] [PMID: 14664702]

[49]
Ward NL, Dumont DJ. The angiopoietins and Tie2/Tek: Adding to the complexity of cardiovascular development. Semin Cell Dev Biol  2002; 13(1): 19-27.
 [http://dx.doi.org/10.1006/scdb.2001.0288] [PMID: 11969368]

[50]
Holash J, Maisonpierre PC, Compton D, et al. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science  1999; 284(5422): 1994-8.
 [http://dx.doi.org/10.1126/science.284.5422.1994] [PMID: 10373119]

[51]
Tadros A, Hughes DP, Dunmore BJ, Brindle NPJ. ABIN-2 protects endothelial cells from death and has a role in the antiapoptotic effect of angiopoietin-1. Blood  2003; 102(13): 4407-9.
 [http://dx.doi.org/10.1182/blood-2003-05-1602] [PMID: 12933576]

[52]
Figueiredo A, Cordeiro AL, Tomada N, et al. Real-time PCR study of Ang1, Ang2, Tie-2, VEGF, and KDR expression in human erectile tissue during aging. J Sex Med  2011; 8(5): 1341-51.
 [http://dx.doi.org/10.1111/j.1743-6109.2010.02116.x] [PMID: 21091880]

[53]
Kwon MH, Ryu JK, Kim WJ, et al. Effect of intracavernous administration of angiopoietin-4 on erectile function in the streptozotocin-induced diabetic mouse. J Sex Med  2013; 10(12): 2912-27.
 [http://dx.doi.org/10.1111/jsm.12278] [PMID: 23937122]

[54]
Jin HR, Kim WJ, Song JS, et al. Intracavernous delivery of a designed angiopoietin-1 variant rescues erectile function by enhancing endothelial regeneration in the streptozotocin-induced diabetic mouse. Diabetes  2011; 60(3): 969-80.
 [http://dx.doi.org/10.2337/db10-0354] [PMID: 21270241]

[55]
Jin HR, Kim WJ, Song JS, et al. Intracavernous delivery of synthetic angiopoietin-1 protein as a novel therapeutic strategy for erectile dysfunction in the type II diabetic db/db mouse. J Sex Med  2010; 7(11): 3635-46.
 [http://dx.doi.org/10.1111/j.1743-6109.2010.01925.x] [PMID: 20584113]

[56]
Mohamed R, El-Remessy AB. Imbalance of the nerve growth factor and its precursor: Implication in diabetic retinopathy. J Clin Exp Ophthalmol  2015; 6(5): 483.
 [http://dx.doi.org/10.4172/2155-9570.1000483] [PMID: 26807305]

[57]
Burgers JK, Nelson RJ, Quinlan DM, Walsh PC. Nerve growth factor, nerve grafts and amniotic membrane grafts restore erectile function in rats. J Urol  1991; 146(2 Part 1): 463-8.
 [http://dx.doi.org/10.1016/S0022-5347(17)37825-4] [PMID: 1856953]

[58]
Bakircioglu ME, Lin CS, Fan P, Sievert KD, Kan YW, Lue F. The effect of adeno-associated virus mediated brain derived neurotrophic factor in an animal model of neurogenic impotence. J Urol  2001; 165(6 Part 1): 2103-9.
 [http://dx.doi.org/10.1016/S0022-5347(05)66302-1] [PMID: 11371936]

[59]
Azadzoi KM, Golabek T, Radisavljevic ZM, Yalla SV, Siroky MB. Oxidative stress and neurodegeneration in penile ischaemia. BJU Int  2010; 105(3): 404-10.
 [http://dx.doi.org/10.1111/j.1464-410X.2009.08717.x] [PMID: 19549113]

[60]
Lee CH, Kim HS, Goo MJ, et al. Chronic administration of udenafil, a selective phosphodiesterase type 5 inhibitor, promotes erectile function recovery in an animal model of bilateral cavernous nerve crush injury. J Sex Med  2011; 8(5): 1330-40.
 [http://dx.doi.org/10.1111/j.1743-6109.2011.02228.x] [PMID: 21366883]

[61]
Wellmer A, Misra VP, Sharief MK, Kopelman PG, Anand P. A double‐blind placebo‐controlled clinical trial of recombinant human brain‐derived neurotrophic factor (rhBDNF) in diabetic polyneuropathy. J Peripher Nerv Syst  2001; 6(4): 204-10.
 [http://dx.doi.org/10.1046/j.1529-8027.2001.01019.x] [PMID: 11800042]

[62]
Zhang HY, Jin XB, Lue TF. Three important components in the regeneration of the cavernous nerve: Brain-derived neurotrophic factor, vascular endothelial growth factor and the JAK/STAT signaling pathway. Asian J Androl  2011; 13(2): 231-5.
 [http://dx.doi.org/10.1038/aja.2010.162] [PMID: 21170078]

[63]
Hsieh PS, Bochinski DJ, Lin GT, Nunes L, Lin CS, Lue TF. The effect of vascular endothelial growth factor and brain‐derived neurotrophic factor on cavernosal nerve regeneration in a nerve‐crush rat model. BJU Int  2003; 92(4): 470-5.
 [http://dx.doi.org/10.1046/j.1464-410X.2003.04373.x] [PMID: 12930443]

[64]
Bennett N, Kim JH, Wolfe DP, et al. Improvement in erectile dysfunction after neurotrophic factor gene therapy in diabetic rats. J Urol  2005; 173(5): 1820-4.
 [http://dx.doi.org/10.1097/01.ju.0000158056.66236.1f] [PMID: 15821595]

[65]
Cao Z, Liu Y, Wang Y, Leng P. Research progress on the role of PDGF/PDGFR in type 2 diabetes. Biomed Pharmacother  2023; 164: 114983.
 [http://dx.doi.org/10.1016/j.biopha.2023.114983] [PMID: 37290188]

[66]
Kim JY, Kim KH, Lee WR, et al. Apamin inhibits PDGF-BB-induced vascular smooth muscle cell proliferation and migration through suppressions of activated Akt and Erk signaling pathway. Vascul Pharmacol  2015; 70: 8-14.
 [http://dx.doi.org/10.1016/j.vph.2014.12.004] [PMID: 25737404]

[67]
Ribeiro-Rodrigues TM, Martins-Marques T, Morel S, Kwak BR, Girão H. Role of connexin 43 in different forms of intercellular communication – gap junctions, extracellular vesicles and tunnelling nanotubes. J Cell Sci  2017; 130(21): jcs.200667.
 [http://dx.doi.org/10.1242/jcs.200667] [PMID: 29025971]

[68]
Zhao F, Yan J, Zhao J, et al. Effect of platelet-derived growth factor-BB on gap junction and connexin43 in rat penile corpus cavernosum smooth muscle cells. Andrologia  2019; 51(3): e13200.
 [http://dx.doi.org/10.1111/and.13200] [PMID: 30467872]

[69]
Korsmeyer SJ, Shutter JR, Veis DJ, Merry DE, Oltvai ZN. Bcl-2/Bax: A rheostat that regulates an anti-oxidant pathway and cell death. Semin Cancer Biol  1993; 4(6): 327-32.
 [PMID: 8142617]

[70]
Yamanaka M, Shirai M, Shiina H, et al. Diabetes induced erectile dysfunction and apoptosis in penile crura are recovered by insulin treatment in rats. J Urol  2003; 170(1): 291-7.
 [http://dx.doi.org/10.1097/01.ju.0000060564.31122.2a] [PMID: 12796708]

[71]
Park K, Ryu KS, Li WJ, Kim SW, Paick JS. Chronic treatment with a type 5 phosphodiesterase inhibitor suppresses apoptosis of corporal smooth muscle by potentiating Akt signalling in a rat model of diabetic erectile dysfunction. Eur Urol  2008; 53(6): 1282-9.
 [http://dx.doi.org/10.1016/j.eururo.2008.01.032] [PMID: 18243503]

[72]
Li WJ, Zhou J, Li B, Wang H, Peng YB, Wang Z. PARP inhibition restores erectile function by suppressing corporal smooth muscle apoptosis in diabetic rats. J Sex Med  2011; 8(4): 1072-82.
 [http://dx.doi.org/10.1111/j.1743-6109.2010.02176.x] [PMID: 21235725]

[73]
Osaki M, Oshimura M, Ito H. PI3K-Akt pathway: Its functions and alterations in human cancer. Apoptosis  2004; 9(6): 667-76.
 [http://dx.doi.org/10.1023/B:APPT.0000045801.15585.dd] [PMID: 15505410]

[74]
Jeon S, Zhu G, Bae W, et al. Engineered Mesenchymal Stem Cells Expressing Stromal Cell-derived Factor-1 Improve Erectile Dysfunction in Streptozotocin-Induced Diabetic Rats. Int J Mol Sci  2018; 19(12): 3730.
 [http://dx.doi.org/10.3390/ijms19123730] [PMID: 30477146]

[75]
Alici B, Gümüstas MK, Özkara H, et al. Apoptosis in the erectile tissues of diabetic and healthy rats. BJU Int  2000; 85(3): 326-9.
 [http://dx.doi.org/10.1046/j.1464-410x.2000.00420.x] [PMID: 10671892]

[76]
Li WJ, Park K, Paick JS, Kim SW. Chronic treatment with an oral rho-kinase inhibitor restores erectile function by suppressing corporal apoptosis in diabetic rats. J Sex Med  2011; 8(2): 400-10.
 [http://dx.doi.org/10.1111/j.1743-6109.2010.01724.x] [PMID: 20233282]

[77]
Song N-H, Wang Y, Meng X-H, et al. Losartan improves erectile function through suppression of corporal apoptosis and oxidative stress in rats with cavernous nerve injury. Asian J Androl  2019; 21(5): 452-9.
 [http://dx.doi.org/10.4103/aja.aja_8_19] [PMID: 30880689]

[78]
Zhou X, Wang S, Zhou R, et al. Erectile dysfunction in hypospadiac male adult rats induced by maternal exposure to di-n-butyl phthalate. Toxicology  2022; 475: 153227.
 [http://dx.doi.org/10.1016/j.tox.2022.153227] [PMID: 35690178]

[79]
Zhu S, Xiong Y, Yu B, et al. Vitamin D3 improved erectile function recovery by regulating autophagy and apoptosis in a rat model of cavernous nerve injury. Int J Impot Res 2023.
 [http://dx.doi.org/10.1038/s41443-023-00679-4] [PMID: 36813836]

[80]
Kendirci M, Zsengellér Z, Bivalacqua TJ, et al. Poly(Adenosine diphosphate-ribose) polymerase inhibition preserves erectile function in rats after cavernous nerve injury. J Urol  2005; 174(5): 2054-9.
 [http://dx.doi.org/10.1097/01.ju.0000176484.35636.e5] [PMID: 16217393]

[81]
Wan ZH, Li WZ, Li YZ, et al. Poly(ADP-Ribose) polymerase inhibition improves erectile function in diabetic rats. J Sex Med  2011; 8(4): 1002-14.
 [http://dx.doi.org/10.1111/j.1743-6109.2010.01963.x] [PMID: 20807334]

[82]
Li WJ, Peng Y, Zhou J, et al. Poly(ADP-ribose) polymerase inhibition improves erectile function by activation of nitric oxide/cyclic guanosine monophosphate pathway in diabetic rats. J Sex Med  2012; 9(5): 1319-27.
 [http://dx.doi.org/10.1111/j.1743-6109.2012.02666.x] [PMID: 22429732]

[83]
Nangle MR, Cotter MA, Cameron NE. Poly(ADP-ribose) polymerase inhibition reverses nitrergic neurovascular dysfunctions in penile erectile tissue from streptozotocin-diabetic mice. J Sex Med  2010; 7(10): 3396-403.
 [http://dx.doi.org/10.1111/j.1743-6109.2010.01835.x] [PMID: 20456626]

[84]
LoRusso PM. Inhibition of the PI3K/AKT/mTOR Pathway in Solid Tumors. J Clin Oncol  2016; 34(31): 3803-15.
 [http://dx.doi.org/10.1200/JCO.2014.59.0018] [PMID: 27621407]

[85]
Hurt KJ, Musicki B, Palese MA, et al. Akt-dependent phosphorylation of endothelial nitric-oxide synthase mediates penile erection. Proc Natl Acad Sci USA  2002; 99(6): 4061-6.
 [http://dx.doi.org/10.1073/pnas.052712499] [PMID: 11904450]

[86]
Musicki B, Kramer MF, Becker RE, Burnett AL. Inactivation of phosphorylated endothelial nitric oxide synthase (Ser-1177) by O -GlcNAc in diabetes-associated erectile dysfunction. Proc Natl Acad Sci USA  2005; 102(33): 11870-5.
 [http://dx.doi.org/10.1073/pnas.0502488102] [PMID: 16085713]

[87]
Wang J, Deng S, Zhao Q, et al. A Bioinformatic Investigation of the Mechanism Underlying Migraine-Induced Erectile Dysfunction. BioMed Res Int  2021; 2021: 1-9.
 [http://dx.doi.org/10.1155/2021/6674643] [PMID: 33997039]

[88]
Li R, Cui K, Liu K, et al. Metabolic syndrome in rats is associated with erectile dysfunction by impairing PI3K/Akt/eNOS activity. Sci Rep  2017; 7(1): 13464.
 [http://dx.doi.org/10.1038/s41598-017-12907-1] [PMID: 29044143]

[89]
Li H, Xu Y, Guan R, et al. Icariside II prevents high-glucose-induced injury on human cavernous endothelial cells through Akt‐ eNOS signaling pathway. Andrology  2015; 3(2): 408-16.
 [http://dx.doi.org/10.1111/andr.303] [PMID: 25641754]

[90]
Wan ZH, Zhang YJ, Chen L, et al. G protein-coupled receptor kinase 2 inhibition improves erectile function through amelioration of endothelial dysfunction and oxidative stress in a rat model of type 2 diabetes. Asian J Androl  2018; 21(1): 74-9.
 [PMID: 30226217]

[91]
Sezen SF, Lagoda G, Musicki B, Burnett AL. Hydroxyl fasudil, an inhibitor of Rho signaling, improves erectile function in diabetic rats: A role for neuronal ROCK. J Sex Med  2014; 11(9): 2164-71.
 [http://dx.doi.org/10.1111/jsm.12613] [PMID: 24919622]

[92]
Contreras C, Sánchez A, Martínez P, et al. Insulin resistance in penile arteries from a rat model of metabolic syndrome. Br J Pharmacol  2010; 161(2): 350-64.
 [http://dx.doi.org/10.1111/j.1476-5381.2010.00825.x] [PMID: 20735420]

[93]
Kong X, Jiang J, Cheng B, Jiang R. Effect of low androgen status on the expression of adenosine A 2A and A 2B receptors in rat penile corpus cavernosum. Andrologia  2019; 51(9): e13344.
 [http://dx.doi.org/10.1111/and.13344] [PMID: 31206753]

[94]
Cui K, Li R, Liu K, Wang T, Liu J, Rao K. Testosterone preserves endothelial function through regulation of S1P1/Akt/FOXO3a signalling pathway in the rat corpus cavernosum. Andrologia  2019; 51(1): e13173.
 [http://dx.doi.org/10.1111/and.13173] [PMID: 30311248]

[95]
Pearson G, Robinson F, Beers Gibson T, et al. Mitogen-activated protein (MAP) kinase pathways: Regulation and physiological functions. Endocr Rev  2001; 22(2): 153-83.
 [PMID: 11294822]

[96]
Toque HA, Romero MJ, Tostes RC, et al. p38 Mitogen-activated protein kinase (MAPK) increases arginase activity and contributes to endothelial dysfunction in corpora cavernosa from angiotensin-II-treated mice. J Sex Med  2010; 7(12): 3857-67.
 [http://dx.doi.org/10.1111/j.1743-6109.2010.01996.x] [PMID: 20807329]

[97]
Nunes KP, Toque HA, Caldwell RB, William Caldwell R, Clinton Webb R. Extracellular signal-regulated kinase (ERK) inhibition decreases arginase activity and improves corpora cavernosal relaxation in streptozotocin (STZ)-induced diabetic mice. J Sex Med  2011; 8(12): 3335-44.
 [http://dx.doi.org/10.1111/j.1743-6109.2011.02499.x] [PMID: 21995824]

[98]
Cho MC, Song WH, Son H, Kim SW, Paick J-S. Role of Jun amino-terminal kinase (JNK) in apoptosis of cavernosal tissue during acute phase after cavernosal nerve injury. Asian J Androl  2018; 20(1): 50-5.
 [http://dx.doi.org/10.4103/aja.aja_10_17] [PMID: 28440265]

[99]
Liu K, Sun T, Luan Y, et al. Berberine ameliorates erectile dysfunction in rats with streptozotocin‐induced diabetes mellitus through the attenuation of apoptosis by inhibiting the SPHK1/S1P/S1PR2 and MAPK pathways. Andrology  2022; 10(2): 404-18.
 [http://dx.doi.org/10.1111/andr.13119] [PMID: 34674380]

[100]
Abdel Aziz MT, Rezq AM, Atta HM, et al. Molecular signalling of a novel curcumin derivative versus Tadalafil in erectile dysfunction. Andrologia  2015; 47(6): 616-25.
 [http://dx.doi.org/10.1111/and.12309] [PMID: 25059462]

[101]
Xu Y, Guan R, Lei H, et al. Implications for differentiation of endogenous stem cells: Therapeutic effect from icariside II on a rat model of postprostatectomy erectile dysfunction. Stem Cells Dev  2015; 24(6): 747-55.
 [http://dx.doi.org/10.1089/scd.2014.0380] [PMID: 25365340]

[102]
Zhang J, Hui Y, Zhou F, Hou JQ. Neuroprotective effects of melatonin on erectile dysfunction in streptozotocin-induced diabetic rats. Int Urol Nephrol  2018; 50(11): 1981-8.
 [http://dx.doi.org/10.1007/s11255-018-1989-4] [PMID: 30242548]

[103]
Liu Y, Pan X, Zhang X, et al. Role of mechanotransduction mediated by YAP/TAZ in the treatment of neurogenic erectile dysfunction with low‐intensity pulsed ultrasound. Andrology  2023; 11(7): 1514-27.
 [http://dx.doi.org/10.1111/andr.13438] [PMID: 37042189]

[104]
Chen S, Huang X, Kong X, et al. Hypoxia-Induced Phenotypic Transformation of Corpus Cavernosum Smooth Muscle Cells After Cavernous Nerve Crush Injury by Down-Regulating P38 Mitogen-Activated Protein Kinase Expression. Sex Med  2019; 7(4): 433-40.
 [http://dx.doi.org/10.1016/j.esxm.2019.08.005] [PMID: 31540881]

[105]
Shaul YD, Seger R. The MEK/ERK cascade: From signaling specificity to diverse functions. Biochim Biophys Acta Mol Cell Res  2007; 1773(8): 1213-26.
 [http://dx.doi.org/10.1016/j.bbamcr.2006.10.005] [PMID: 17112607]

[106]
Sommer F, Klotz T, Steinritz D, et al. MAP kinase 1/2 (Erk 1/2) and serine/threonine specific protein kinase Akt/PKB expression and activity in the human corpus cavernosum. Int J Impot Res  2002; 14(4): 217-25.
 [http://dx.doi.org/10.1038/sj.ijir.3900856] [PMID: 12152110]

[107]
Lysiak JJ, Yang SK, Klausner AP, Son H, Tuttle JB, Steers WD. Tadalafil increases Akt and extracellular signal-regulated kinase 1/2 activation, and prevents apoptotic cell death in the penis following denervation. J Urol  2008; 179(2): 779-85.
 [http://dx.doi.org/10.1016/j.juro.2007.09.021] [PMID: 18082193]

[108]
Park J, Chai JS, Kim SW, Paick JS, Cho MC. Inhibition of Jun N-terminal kinase improves erectile function by alleviation of cavernosal apoptosis in a rat model of cavernous nerve injury. Urology  2018; 113: 253.

[109]
Castela Â, Soares R, Rocha F, Vendeira P, Virag R, Costa C. Erectile tissue molecular alterations with aging—differential activation of the p42/44 MAP Kinase pathway. Age (Omaha)  2011; 33(2): 119-30.
 [http://dx.doi.org/10.1007/s11357-010-9167-3] [PMID: 20628826]

[110]
Xin P, Xu X, Deng C, et al. The role of JAK/STAT signaling pathway and its inhibitors in diseases. Int Immunopharmacol  2020; 80: 106210.
 [http://dx.doi.org/10.1016/j.intimp.2020.106210] [PMID: 31972425]

[111]
Song J, Tang Z, Li H, et al. Role of JAK2 in the Pathogenesis of Diabetic Erectile Dysfunction and an Intervention With Berberine. J Sex Med  2019; 16(11): 1708-20.
 [http://dx.doi.org/10.1016/j.jsxm.2019.08.014] [PMID: 31564534]

[112]
Xi YJ, Wen R, Zhang R, et al. Causal association between JAK2 and erectile dysfunction: A Mendelian randomization study. Basic Clin Androl  2023; 33(1): 18.
 [http://dx.doi.org/10.1186/s12610-023-00192-0] [PMID: 37407943]

[113]
Bella AJ, Lin G, Tantiwongse K, et al. Brain-derived neurotrophic factor (BDNF) acts primarily via the JAK/STAT pathway to promote neurite growth in the major pelvic ganglion of the rat: Part I. J Sex Med  2006; 3(5): 815-20.
 [http://dx.doi.org/10.1111/j.1743-6109.2006.00291.x] [PMID: 16942526]

[114]
Bella AJ, Lin G, Garcia MM, et al. Upregulation of penile brain-derived neurotrophic factor (BDNF) and activation of the JAK/STAT signalling pathway in the major pelvic ganglion of the rat after cavernous nerve transection. Eur Urol  2007; 52(2): 574-81.
 [http://dx.doi.org/10.1016/j.eururo.2006.10.043] [PMID: 17097800]

[115]
Valenta T, Hausmann G, Basler K. The many faces and functions of β-catenin. EMBO J  2012; 31(12): 2714-36.
 [http://dx.doi.org/10.1038/emboj.2012.150] [PMID: 22617422]

[116]
ten Dam EJPM, van Driel MF, de Jong IJ, Werker PMN, Bank RA. Glimpses into the molecular pathogenesis of Peyronie’s disease. Aging Male  2020; 23(5): 962-70.
 [http://dx.doi.org/10.1080/13685538.2019.1643311] [PMID: 31335242]

[117]
De Young LX, Bella AJ, O’Gorman DB, Gan BS, Lim KB, Brock GB. Protein biomarker analysis of primary Peyronie’s disease cells. J Sex Med  2010; 7(1_Part_1): 99-106.
 [http://dx.doi.org/10.1111/j.1743-6109.2009.01556.x] [PMID: 19889147]

[118]
Takahashi-Yanaga F, Sasaguri T. GSK-3β regulates cyclin D1 expression: A new target for chemotherapy. Cell Signal  2008; 20(4): 581-9.
 [http://dx.doi.org/10.1016/j.cellsig.2007.10.018] [PMID: 18023328]

[119]
Gu S, Li M, Yuan Y, Xin Z, Guan R. A novel flavonoid derivative of icariside II improves erectile dysfunction in a rat model of cavernous nerve injury. Andrology  2021; 9(6): 1893-901.
 [http://dx.doi.org/10.1111/andr.13065] [PMID: 34106520]

[120]
Shin SH, Kim WJ, Choi MJ, et al. Aberrant expression of Wnt family contributes to the pathogenesis of diabetes‐induced erectile dysfunction. Andrology  2014; 2(1): 107-16.
 [http://dx.doi.org/10.1111/j.2047-2927.2013.00162.x] [PMID: 24265248]

[121]
Baron R, Kneissel M. WNT signaling in bone homeostasis and disease: From human mutations to treatments. Nat Med  2013; 19(2): 179-92.
 [http://dx.doi.org/10.1038/nm.3074] [PMID: 23389618]

[122]
Kawano Y, Kypta R. Secreted antagonists of the Wnt signalling pathway. J Cell Sci  2003; 116(13): 2627-34.
 [http://dx.doi.org/10.1242/jcs.00623] [PMID: 12775774]

[123]
Liang X, Jin Q, Yang X, Jiang W. Dickkopf 3 and β catenin play opposite roles in the Wnt/β catenin pathway during the abnormal subchondral bone formation of human knee osteoarthritis. Int J Mol Med  2022; 49(4): 48.
 [http://dx.doi.org/10.3892/ijmm.2022.5103] [PMID: 35137918]

[124]
Yin GN, Jin HR, Choi MJ, et al. Pericyte-Derived Dickkopf2 Regenerates Damaged Penile Neurovasculature Through an Angiopoietin-1-Tie2 Pathway. Diabetes  2018; 67(6): 1149-61.
 [http://dx.doi.org/10.2337/db17-0833] [PMID: 29559443]

[125]
Ghatak K, Yin GN, Choi MJ, et al. Dickkopf2 rescues erectile function by enhancing penile neurovascular regeneration in a mouse model of cavernous nerve injury. Sci Rep  2017; 7(1): 17819.
 [http://dx.doi.org/10.1038/s41598-017-17862-5] [PMID: 29259207]

[126]
Song KM, Kim WJ, Choi MJ, et al. Intracavernous delivery of Dickkopf3 gene or peptide rescues erectile function through enhanced cavernous angiogenesis in the diabetic mouse. Andrology  2020; 8(5): 1387-97.
 [http://dx.doi.org/10.1111/andr.12784] [PMID: 32170840]

[127]
Podlasek CA, Zelner DJ, Jiang HB, et al. Sonic hedgehog cascade is required for penile postnatal morphogenesis, differentiation, and adult homeostasis. Biol Reprod  2003; 68(2): 423-38.
 [http://dx.doi.org/10.1095/biolreprod.102.006643] [PMID: 12533405]

[128]
Podlasek CA. Sonic hedgehog, apoptosis, and the penis. J Sex Med  2009; 6 (Suppl. 3): 334-9.

[129]
Podlasek C, Meroz C, Korolis H, Tang Y, McKenna K, McVary K. Sonic hedgehog, the penis and erectile dysfunction: A review of sonic hedgehog signaling in the penis. Curr Pharm Des  2005; 11(31): 4011-27.
 [http://dx.doi.org/10.2174/138161205774913408] [PMID: 16378507]

[130]
Podlasek CA, Meroz CL, Tang Y, McKenna KE, McVary KT. Regulation of cavernous nerve injury-induced apoptosis by sonic hedgehog. Biol Reprod  2007; 76(1): 19-28.
 [http://dx.doi.org/10.1095/biolreprod.106.053926] [PMID: 16988214]

[131]
Bond C, Cakir OO, McVary KT, Podlasek CA. Nitric Oxide Synthase is Necessary for Normal Urogenital Development. Andrology (Los Angel)  2013; 2: 108.
 [PMID: 24900949]

[132]
Martin S, Harrington DA, Ohlander S, Stupp SI, McVary KT, Podlasek CA. Peptide amphiphile nanofiber hydrogel delivery of Sonic hedgehog protein to the penis and cavernous nerve suppresses intrinsic and extrinsic apoptotic signaling mechanisms, which are an underlying cause of erectile dysfunction. Nanomedicine  2021; 37: 102444.
 [http://dx.doi.org/10.1016/j.nano.2021.102444] [PMID: 34314869]

[133]
Bond C, Tang Y, Podlasek CA. Neural influences on sonic hedgehog and apoptosis in the rat penis. Biol Reprod  2008; 78(5): 947-56.
 [http://dx.doi.org/10.1095/biolreprod.107.064766] [PMID: 18256331]

[134]
Choe S, Veliceasa D, Bond CW, et al. Sonic hedgehog delivery from self-assembled nanofiber hydrogels reduces the fibrotic response in models of erectile dysfunction. Acta Biomater  2016; 32: 89-99.
 [http://dx.doi.org/10.1016/j.actbio.2016.01.014] [PMID: 26776147]

[135]
Angeloni NL, Bond CW, Tang Y, et al. Regeneration of the cavernous nerve by Sonic hedgehog using aligned peptide amphiphile nanofibers. Biomaterials  2011; 32(4): 1091-101.
 [http://dx.doi.org/10.1016/j.biomaterials.2010.10.003] [PMID: 20971506]

[136]
Dobbs R, Choe S, Kalmanek E, et al. Peptide amphiphile delivery of sonic hedgehog protein promotes neurite formation in penile projecting neurons. Nanomedicine  2018; 14(7): 2087-94.
 [http://dx.doi.org/10.1016/j.nano.2018.06.006] [PMID: 30037776]

[137]
Podlasek CA, Zelner DJ, Harris JD, et al. Altered Sonic hedgehog signaling is associated with morphological abnormalities in the penis of the BB/WOR diabetic rat. Biol Reprod  2003; 69(3): 816-27.
 [http://dx.doi.org/10.1095/biolreprod.102.013508] [PMID: 12748119]

[138]
Dobbs R, Kalmanek E, Choe S, et al. Sonic hedgehog regulation of cavernous nerve regeneration and neurite formation in aged pelvic plexus. Exp Neurol  2019; 312: 10-9.
 [http://dx.doi.org/10.1016/j.expneurol.2018.11.001] [PMID: 30391523]

[139]
Angeloni NL, Bond CW, McVary KT, Podlasek CA. Sonic hedgehog protein is decreased and penile morphology is altered in prostatectomy and diabetic patients. PLoS One  2013; 8(8): e70985.
 [http://dx.doi.org/10.1371/journal.pone.0070985] [PMID: 23967143]

[140]
Moya IM, Halder G. Hippo–YAP/TAZ signalling in organ regeneration and regenerative medicine. Nat Rev Mol Cell Biol  2019; 20(4): 211-26.
 [http://dx.doi.org/10.1038/s41580-018-0086-y] [PMID: 30546055]

[141]
Li H, Wu BK, Kanchwala M, et al. YAP/TAZ drives cell proliferation and tumour growth via a polyamine–eIF5A hypusination–LSD1 axis. Nat Cell Biol  2022; 24(3): 373-83.
 [http://dx.doi.org/10.1038/s41556-022-00848-5] [PMID: 35177822]

[142]
Zhao B, Ye X, Yu J, et al. TEAD mediates YAP-dependent gene induction and growth control. Genes Dev  2008; 22(14): 1962-71.
 [http://dx.doi.org/10.1101/gad.1664408] [PMID: 18579750]

[143]
Milenkovic U, Ilg MM, Zuccato C, Ramazani Y, De Ridder D, Albersen M. Simvastatin and the Rho‐kinase inhibitor Y‐27632 prevent myofibroblast transformation in Peyronie’s disease‐derived fibroblasts via inhibition of YAP/TAZ nuclear translocation. BJU Int  2019; 123(4): 703-15.
 [http://dx.doi.org/10.1111/bju.14638] [PMID: 30536599]

[144]
Zhao L, Han S, Su H, et al. Single-cell transcriptome atlas of the human corpus cavernosum. Nat Commun  2022; 13(1): 4302.
 [http://dx.doi.org/10.1038/s41467-022-31950-9] [PMID: 35879305]

[145]
Ji M, Chen D, Shu Y, et al. The role of mechano-regulated YAP/TAZ in erectile dysfunction. Nat Commun  2023; 14(1): 3758.
 [http://dx.doi.org/10.1038/s41467-023-39009-z] [PMID: 37353497]

[146]
Shishodia S, Aggarwal BB. Nuclear factor-kappaB activation: A question of life or death. J Biochem Mol Biol  2002; 35(1): 28-40.
 [PMID: 16248967]

[147]
Yamamoto Y, Gaynor RB. IκB kinases: Key regulators of the NF-κB pathway. Trends Biochem Sci  2004; 29(2): 72-9.
 [http://dx.doi.org/10.1016/j.tibs.2003.12.003] [PMID: 15102433]

[148]
Lawrence T. The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb Perspect Biol  2009; 1(6): a001651.
 [http://dx.doi.org/10.1101/cshperspect.a001651] [PMID: 20457564]

[149]
Angulo J, Peiró C, Cuevas P, et al. The novel antioxidant, AC3056 (2,6-di-t-butyl-4-((dimethyl-4-methoxyphenylsilyl)methyloxy)phenol), reverses erectile dysfunction in diabetic rats and improves NO-mediated responses in penile tissue from diabetic men. J Sex Med  2009; 6(2): 373-87.
 [http://dx.doi.org/10.1111/j.1743-6109.2008.01088.x] [PMID: 19040617]

[150]
Nangle MR, Cotter MA, Cameron NE. IκB kinase 2 inhibition corrects defective nitrergic erectile mechanisms in diabetic mouse corpus cavernosum. Urology  2006; 68(1): 214-8.
 [http://dx.doi.org/10.1016/j.urology.2006.01.065] [PMID: 16806421]

[151]
Ma Z, Wang W, Pan C, et al. N‐acetylcysteine improves diabetic associated erectile dysfunction in streptozotocin‐induced diabetic mice by inhibiting oxidative stress. J Cell Mol Med  2022; 26(12): 3527-37.
 [http://dx.doi.org/10.1111/jcmm.17394] [PMID: 35593216]

[152]
Draganski A, Tar MT, Villegas G, Friedman JM, Davies KP. Topically Applied Curcumin-Loaded Nanoparticles Treat Erectile Dysfunction in a Rat Model of Type-2 Diabetes. J Sex Med  2018; 15(5): 645-53.
 [http://dx.doi.org/10.1016/j.jsxm.2018.03.009] [PMID: 29699754]

[153]
Abdel Aziz MT, Motawi T, Rezq A, et al. Effects of a water-soluble curcumin protein conjugate vs. pure curcumin in a diabetic model of erectile dysfunction. J Sex Med  2012; 9(7): 1815-33.
 [http://dx.doi.org/10.1111/j.1743-6109.2012.02741.x] [PMID: 22548787]

[154]
Leite LN, do Vale GT, Simplicio JA, De Martinis BS, Carneiro FS, Tirapelli CR. Ethanol-induced erectile dysfunction and increased expression of pro-inflammatory proteins in the rat cavernosal smooth muscle are mediated by NADPH oxidase-derived reactive oxygen species. Eur J Pharmacol  2017; 804: 82-93.
 [http://dx.doi.org/10.1016/j.ejphar.2017.03.024] [PMID: 28315342]

[155]
Zaahkouk AMS, Abdel Aziz MT, Rezq AM, et al. Efficacy of a novel water-soluble curcumin derivative versus sildenafil citrate in mediating erectile function. Int J Impot Res  2015; 27(1): 9-15.
 [http://dx.doi.org/10.1038/ijir.2014.24] [PMID: 25099638]

[156]
Freitas M, Rodrigues AR, Tomada N, et al. Effects of Aging and Cardiovascular Disease Risk Factors on the Expression of Sirtuins in the Human Corpus Cavernosum. J Sex Med  2015; 12(11): 2141-52.
 [http://dx.doi.org/10.1111/jsm.13035] [PMID: 26556180]

[157]
Liu T, Zhang L, Joo D, Sun SC. NF-κB signaling in inflammation. Signal Transduct Target Ther  2017; 2(1): 17023.
 [http://dx.doi.org/10.1038/sigtrans.2017.23] [PMID: 29158945]

[158]
An Y, Zhang H, Wang C, et al. Activation of ROS/MAPK s/NF‐ κ B/NLRP3 and inhibition of efferocytosis in osteoclast‐mediated diabetic osteoporosis. FASEB J  2019; 33(11): 12515-27.
 [http://dx.doi.org/10.1096/fj.201802805RR] [PMID: 31461386]

[159]
Zhu B, Niu Y, Niu L, Zhang X, Liu F. Exploring the application of sildenafil for high-fat diet-induced erectile dysfunction based on interleukin-18-mediated NLRP3/Caspase-1 signaling pathway. Sex Med  2023; 11(4): qfad044.
 [http://dx.doi.org/10.1093/sexmed/qfad044] [PMID: 37636019]

[160]
Sun T, Xu W, Wang J, et al. Paeonol ameliorates diabetic erectile dysfunction by inhibiting HMGB1/RAGE/NF‐kB pathway. Andrology  2023; 11(2): 344-57.
 [http://dx.doi.org/10.1111/andr.13203] [PMID: 35678254]

[161]
Shi C-M, Li W-B, Yue X-F, et al. The near-infrared dye IR-61 restores erectile function in a streptozotocin-induced diabetes model via mitochondrial protection. Asian J Androl  2021; 23(3): 249-58.
 [http://dx.doi.org/10.4103/aja.aja_69_20] [PMID: 33402547]

[162]
Fais RS, Rodrigues FL, Pereira CA, et al. The inflammasome NLRP3 plays a dual role on mouse corpora cavernosa relaxation. Sci Rep  2019; 9(1): 16224.
 [http://dx.doi.org/10.1038/s41598-019-52831-0] [PMID: 31700106]

[163]
Ajeigbe OF, Oboh G, Ademosun AO, Umar HI. Fig (Ficus exasperata and Ficus asperifolia)‐Supplemented diet improves sexual function, endothelial nitric oxide synthase and suppresses tumour necrosis factor‐alpha genes in hypertensive rats. Andrologia  2022; 54(1): e14289.
 [http://dx.doi.org/10.1111/and.14289] [PMID: 34693556]

[164]
Adebayo AA, Oboh G, Ademosun AO. Effect of dietary inclusion of almond fruit on sexual behavior, arginase activity, pro‐inflammatory, and oxidative stress markers in diabetic male rats. J Food Biochem  2021; 45(3): e13269.
 [http://dx.doi.org/10.1111/jfbc.13269] [PMID: 32394504]

[165]
Çevikelli-Yakut ZA, Özçelik R, Çevik Ö, Şener TE, Şener G. Exercise and caloric restriction improve cardiovascular and erectile function in rats with metabolic syndrome. Int J Impot Res  2021; 33(8): 844-53.
 [http://dx.doi.org/10.1038/s41443-020-00356-w] [PMID: 33009496]

[166]
Eser N, Yoldaş A, Yigin A, et al. The protective effect of Ferula elaeochytris on age-related erectile dysfunction. J Ethnopharmacol  2020; 258: 112921.
 [http://dx.doi.org/10.1016/j.jep.2020.112921] [PMID: 32387466]

[167]
Akintunde JK, Akintola TE, Aliu FH, Fajoye MO, Adimchi SO. Naringin regulates erectile dysfunction by abolition of apoptosis and inflammation through NOS/cGMP/PKG signalling pathway on exposure to Bisphenol-A in hypertensive rat model. Reprod Toxicol  2020; 95: 123-36.
 [http://dx.doi.org/10.1016/j.reprotox.2020.05.007] [PMID: 32428650]

[168]
Demirtaş Şahin T, Yazir Y, Utkan T, Gacar G, Furat Rençber S, Gocmez SS. TNF-α antagonism with etanercept enhances penile NOS expression, cavernosal reactivity, and testosterone levels in aged rats. Can J Physiol Pharmacol  2018; 96(2): 200-7.
 [http://dx.doi.org/10.1139/cjpp-2017-0113] [PMID: 29260891]

[169]
Alkan E, Ugan RA, Basar MM, et al. Role of endothelin receptors and relationship with nitric oxide synthase in impaired erectile response in diabetic rats. Andrologia  2017; 49(2): e12607.
 [http://dx.doi.org/10.1111/and.12607] [PMID: 27145076]

[170]
Facio FN Jr, Facio MF, Spessoto LF, et al. Anti-inflammatory and anti-fibrotic effects of annexin1 on erectile function after cavernous nerve injury in rats. Int J Impot Res  2016; 28(6): 221-7.
 [http://dx.doi.org/10.1038/ijir.2016.32] [PMID: 27557611]

[171]
Kataoka T, Hotta Y, Maeda Y, Kimura K. Assessment of androgen replacement therapy for erectile function in rats with type 2 diabetes mellitus by examining nitric oxide-related and inflammatory factors. J Sex Med  2014; 11(4): 920-9.
 [http://dx.doi.org/10.1111/jsm.12447] [PMID: 24467772]

[172]
Priviero F, Calmasini F, Dela Justina V, Wenceslau CF, McCarthy CG, Webb RC. Macrophage-Specific Toll Like Receptor 9 (TLR9) Causes Corpus Cavernosum Dysfunction in Mice Fed a High Fat Diet. J Sex Med  2021; 18(4): 723-31.
 [http://dx.doi.org/10.1016/j.jsxm.2021.01.180] [PMID: 33741290]

[173]
Demirtaş Şahin T, Yazir Y, Utkan T, Gacar G, Halbutoğulları ZS, Gocmez SS. Depression induced by chronic stress leads to penile cavernosal dysfunction: Protective effect of anti-TNF-α treatment. Can J Physiol Pharmacol  2018; 96(9): 933-42.
 [http://dx.doi.org/10.1139/cjpp-2017-0778] [PMID: 30052465]

[174]
Carneiro FS, Sturgis LC, Giachini FRC, et al. TNF-alpha knockout mice have increased corpora cavernosa relaxation. J Sex Med  2009; 6(1): 115-25.
 [http://dx.doi.org/10.1111/j.1743-6109.2008.01029.x] [PMID: 19170842]

[175]
Matsui H, Sopko NA, Campbell JD, et al. Increased Level of Tumor Necrosis Factor-Alpha (TNF-α) Leads to Downregulation of Nitrergic Neurons Following Bilateral Cavernous Nerve Injury and Modulates Penile Smooth Tone. J Sex Med  2021; 18(7): 1181-90.
 [http://dx.doi.org/10.1016/j.jsxm.2021.05.001] [PMID: 34274042]

[176]
Carneiro FS, Zemse S, Giachini FR. TNF-alpha infusion impairs corpora cavernosa reactivity. J Sex Med  2009; 6 (Suppl. 3): 311-9.

[177]
Nunes KP, Bomfim GF, Toque HA, Szasz T, Clinton Webb R. Toll-like receptor 4 (TLR4) impairs nitric oxide contributing to Angiotensin II-induced cavernosal dysfunction. Life Sci  2017; 191: 219-26.
 [http://dx.doi.org/10.1016/j.lfs.2017.10.014] [PMID: 29032115]

[178]
Huang T, Wang G, Hu Y, et al. Structural and functional abnormalities of penile cavernous endothelial cells result in erectile dysfunction at experimental autoimmune prostatitis rat. J Inflamm (Lond)  2019; 16(1): 20.
 [http://dx.doi.org/10.1186/s12950-019-0224-0] [PMID: 31372097]

[179]
Şahin TD, Yazır Y, Utkan T, Göçmez SS, Bayramgürler D. Penile constitutive nitric oxide synthase expression in rats exposed to unpredictable chronic mild stress: Role of inflammation. Int J Impot Res  2017; 29(2): 76-81.
 [http://dx.doi.org/10.1038/ijir.2016.50] [PMID: 27904147]

[180]
Vignozzi L, Filippi S, Comeglio P, et al. Nonalcoholic steatohepatitis as a novel player in metabolic syndrome-induced erectile dysfunction: An experimental study in the rabbit. Mol Cell Endocrinol  2014; 384(1-2): 143-54.
 [http://dx.doi.org/10.1016/j.mce.2014.01.014] [PMID: 24486698]

[181]
Long T, Liu G, Wang Y, Chen Y, Zhang Y, Qin D. TNF-α, erectile dysfunction, and NADPH oxidase-mediated ROS generation in corpus cavernosum in high-fat diet/streptozotocin-induced diabetic rats. J Sex Med  2012; 9(7): 1801-14.
 [http://dx.doi.org/10.1111/j.1743-6109.2012.02739.x] [PMID: 22524530]

[182]
Wang ZL, Yang LY, Chen HH, Lin HH, Tsai YT, Huang WJ. Effects of TNF-α on penile structure alteration in rats with hyperprolactinemia. PLoS One  2017; 12(8): e0181952.
 [http://dx.doi.org/10.1371/journal.pone.0181952] [PMID: 28763467]

[183]
Kaya-Sezginer E, Yilmaz-Oral D, Kırlangıç OF, et al. Sodium butyrate ameliorates erectile dysfunction through fibrosis in a rat model of partial bladder outlet obstruction. Andrology  2022; 10(7): 1441-53.
 [http://dx.doi.org/10.1111/andr.13231] [PMID: 35852413]

[184]
Matos G, Hirotsu C, Alvarenga TA, et al. The association between TNF-α and erectile dysfunction complaints. Andrology  2013; 1(6): 872-8.
 [http://dx.doi.org/10.1111/j.2047-2927.2013.00136.x] [PMID: 24123864]

[185]
Vlachopoulos C, Aznaouridis K, Ioakeimidis N, et al. Unfavourable endothelial and inflammatory state in erectile dysfunction patients with or without coronary artery disease. Eur Heart J  2006; 27(22): 2640-8.
 [http://dx.doi.org/10.1093/eurheartj/ehl341] [PMID: 17056702]

[186]
Bouloukaki I, Papadimitriou V, Sofras F, et al. Abnormal cytokine profile in patients with obstructive sleep apnea-hypopnea syndrome and erectile dysfunction. Mediators Inflamm  2014; 2014: 1-7.
 [http://dx.doi.org/10.1155/2014/568951] [PMID: 24966468]

[187]
Araña Rosaínz MJ, Ojeda MO, Acosta JR, et al. Imbalanced low-grade inflammation and endothelial activation in patients with type 2 diabetes mellitus and erectile dysfunction. J Sex Med  2011; 8(7): 2017-30.
 [http://dx.doi.org/10.1111/j.1743-6109.2011.02277.x] [PMID: 21554550]

[188]
Assar ME, Angulo J, García-Rojo E, et al. Early manifestation of aging-related vascular dysfunction in human penile vasculature—A potential explanation for the role of erectile dysfunction as a harbinger of systemic vascular disease. Geroscience  2022; 44(1): 485-501.
 [http://dx.doi.org/10.1007/s11357-021-00507-x] [PMID: 34962617]

[189]
Oh JS, Heo H-M, Kim Y-G, Lee SG, Lee C-K, Yoo B. The effect of anti-tumor necrosis factor agents on sexual dysfunction in male patients with ankylosing spondylitis: A pilot study. Int J Impot Res  2009; 21(6): 372-5.
 [http://dx.doi.org/10.1038/ijir.2009.44] [PMID: 19759542]

[190]
Garcia L, Hlaing S, Gutierrez R, et al. Sildenafil attenuates inflammation and oxidative stress in pelvic ganglia neurons after bilateral cavernosal nerve damage. Int J Mol Sci  2014; 15(10): 17204-20.
 [http://dx.doi.org/10.3390/ijms151017204] [PMID: 25264738]

[191]
Sturny M, Karakus S, Fraga-Silva R, Stergiopulos N, Burnett AL. Low-intensity electrostimulation enhances neuroregeneration and improves erectile function in a rat model of cavernous nerve injury. J Sex Med  2022; 19(5): 686-96.
 [http://dx.doi.org/10.1016/j.jsxm.2022.02.004] [PMID: 35288047]

[192]
Kishimoto T, Kataoka T, Yamamoto Y, et al. High salt intake impairs erectile function in salt-sensitive rats through mineralocorticoid receptor pathway beyond its effect on blood pressure. J Sex Med  2020; 17(7): 1280-7.
 [http://dx.doi.org/10.1016/j.jsxm.2020.04.384] [PMID: 32624131]

[193]
Yamashita S, Kato R, Kobayashi K, Hisasue S, Arai Y, Tsukamoto T. Inhibition of interleukin-6 attenuates erectile dysfunction in a rat model of nerve-sparing radical prostatectomy. J Sex Med  2011; 8(7): 1957-64.
 [http://dx.doi.org/10.1111/j.1743-6109.2011.02283.x] [PMID: 21492407]

[194]
Ben Khedher MR, Bouhajja H, Haj Ahmed S, Abid M, Jamoussi K, Hammami M. Role of disturbed fatty acids metabolism in the pathophysiology of diabetic erectile dysfunction. Lipids Health Dis  2017; 16(1): 241.
 [http://dx.doi.org/10.1186/s12944-017-0637-9] [PMID: 29233142]

[195]
Vlachopoulos C, Aznaouridis K, Ioakeimidis N, et al. Arterial function and intima-media thickness in hypertensive patients with erectile dysfunction. J Hypertens  2008; 26(9): 1829-36.
 [http://dx.doi.org/10.1097/HJH.0b013e3283050886] [PMID: 18698219]

[196]
Sivritepe R, Uçak Basat S, Baygul A, Küçük EV. The effect of interleukin‐6 level at the time of hospitalisation on erectile functions in hospitalised patients with COVID‐19. Andrologia  2022; 54(1): e14285.
 [http://dx.doi.org/10.1111/and.14285] [PMID: 34687052]

[197]
Shi M-D, Chao J-K, Ma M-C, Chiang S-K, Chao I-C. The connection between type 2 diabetes and erectile dysfunction in Taiwanese aboriginal males. Int J Impot Res  2014; 26(6): 235-40.
 [http://dx.doi.org/10.1038/ijir.2014.26] [PMID: 25078051]

[198]
Giugliano F, Esposito K, Di Palo C, et al. Erectile dysfunction associates with endothelial dysfunction and raised proinflammatory cytokine levels in obese men. J Endocrinol Invest  2004; 27(7): 665-9.
 [http://dx.doi.org/10.1007/BF03347500] [PMID: 15505991]

[199]
MacMicking J, Xie Q, Nathan C. Nitric oxide and macrophage function. Annu Rev Immunol  1997; 15(1): 323-50.
 [http://dx.doi.org/10.1146/annurev.immunol.15.1.323] [PMID: 9143691]

[200]
Macit C, Ustundag UV, Dagdeviren OC, Mercanoglu G, Sener G. The effects of calorie restriction and exercise on age-related alterations in corpus cavernosum. Front Physiol  2020; 11: 45.
 [http://dx.doi.org/10.3389/fphys.2020.00045] [PMID: 32132927]

[201]
Usta MF, Gurbuz N, Kol A, Ipekci T, Ates E, Baykal A. Chronic administration of sildenafil improves erectile function in a rat model of chronic renal failure. Asian J Androl  2015; 17(5): 797-801.
 [http://dx.doi.org/10.4103/1008-682X.146973] [PMID: 25652632]

[202]
Xu Y, Zhang F, Li C, Hao H, Hao Y. Angiotensin-(1−7) improves diabetes mellitus-induced erectile dysfunction in rats by regulating nitric oxide synthase levels. Peptides  2022; 151: 170765.
 [http://dx.doi.org/10.1016/j.peptides.2022.170765] [PMID: 35181349]

[203]
Cheng YS, Cong XD, Dai DZ, Zhang Y, Dai Y. Argirein alleviates corpus cavernosum dysfunction by suppressing pro-inflammatory factors p66Shc and ER stress chaperone Bip in diabetic rats. J Pharm Pharmacol  2012; 65(1): 94-101.
 [http://dx.doi.org/10.1111/j.2042-7158.2012.01565.x] [PMID: 23215692]

[204]
Liu K, Liu XS, Xiao L, et al. NADPH oxidase activation: A mechanism of erectile dysfunction in a rat model of sleep apnea. J Androl  2012; 33(6): 1186-98.
 [http://dx.doi.org/10.2164/jandrol.112.016642] [PMID: 22653964]

[205]
Gurbuz N, Sagdic G, Sanli A, et al. Therapeutic effect of combination of alagebrium (ALT-711) and sildenafil on erectile function in diabetic rats. Int J Impot Res  2012; 24(3): 114-21.
 [http://dx.doi.org/10.1038/ijir.2011.54] [PMID: 22205245]

[206]
Gur S, Kadowitz PJ, Gurkan L, et al. Chronic inhibition of nitric‐oxide synthase induces hypertension and erectile dysfunction in the rat that is not reversed by sildenafil. BJU Int  2010; 106(1): 78-83.
 [http://dx.doi.org/10.1111/j.1464-410X.2009.09104.x] [PMID: 20002674]

[207]
Lizarte FS, Morgueti M, Tirapelli CR, et al. Chronic alcoholism associated with diabetes impairs erectile function in rats. BJU Int  2010; 105(11): 1592-7.
 [http://dx.doi.org/10.1111/j.1464-410X.2009.09084.x] [PMID: 20132198]

[208]
Kawakami T, Urakami S, Hirata H, et al. Superoxide dismutase analog (Tempol: 4-hydroxy-2, 2, 6, 6-tetramethylpiperidine 1-oxyl) treatment restores erectile function in diabetes-induced impotence. Int J Impot Res  2009; 21(6): 348-55.
 [http://dx.doi.org/10.1038/ijir.2009.28] [PMID: 19554009]

[209]
Azadzoi KM, Master TA, Siroky MB. Effect of chronic ischemia on constitutive and inducible nitric oxide synthase expression in erectile tissue. J Androl  2004; 25(3): 382-8.
 [http://dx.doi.org/10.1002/j.1939-4640.2004.tb02804.x] [PMID: 15064316]

[210]
Usta MF, Bivalacqua TJ, Yang DY, et al. The protective effect of aminoguanidine on erectile function in streptozotocin diabetic rats. J Urol  2003; 170(4 Part 1): 1437-42.
 [http://dx.doi.org/10.1097/01.ju.0000077557.45582.f3] [PMID: 14501785]

[211]
Ferrini M, Magee TR, Vernet D, Rajfer J, González-Cadavid NF. Aging-related expression of inducible nitric oxide synthase and markers of tissue damage in the rat penis. Biol Reprod  2001; 64(3): 974-82.
 [http://dx.doi.org/10.1095/biolreprod64.3.974] [PMID: 11207215]

[212]
Bivalacqua TJ, Diner EK, Novak T, et al. A rat model of Peyronie’s disease associated with a decrease in erectile activity and an increase in inducible nitric oxide synthase protein expression. J Urol  2000; 163(6): 1992-8.
 [http://dx.doi.org/10.1016/S0022-5347(05)67616-1] [PMID: 10799245]

[213]
Gur S, Sikka SC, Chandra S, et al. Alfuzosin attenuates erectile dysfunction in rats with partial bladder outlet obstruction. BJU Int  2008; 102(11): 1651-7.
 [http://dx.doi.org/10.1111/j.1464-410X.2008.07914.x] [PMID: 18990166]

[214]
Rocha B, Rodrigues AR, Tomada I, et al. Energy restriction, exercise and atorvastatin treatment improve endothelial dysfunction and inhibit miRNA-155 in the erectile tissue of the aged rat. Nutr Metab (Lond)  2018; 15(1): 28.
 [http://dx.doi.org/10.1186/s12986-018-0265-z] [PMID: 29686722]

[215]
Sawada N, Nomiya M, Zarifpour M, Mitsui T, Takeda M, Andersson KE. Melatonin Improves Erectile Function in Rats with Chronic Lower Body Ischemia. J Sex Med  2016; 13(2): 179-86.
 [http://dx.doi.org/10.1016/j.jsxm.2015.12.018] [PMID: 26803454]

[216]
Leite LN, Lacchini R, Carnio EC, et al. Ethanol consumption increases endothelin-1 expression and reactivity in the rat cavernosal smooth muscle. Alcohol Alcohol  2013; 48(6): 657-66.
 [http://dx.doi.org/10.1093/alcalc/agt057] [PMID: 23797280]

[217]
Ferrini MG, Vernet D, Magee TR, et al. Antifibrotic role of inducible nitric oxide synthase. Nitric Oxide  2002; 6(3): 283-94.
 [http://dx.doi.org/10.1006/niox.2001.0421] [PMID: 12009846]

[218]
Xie D, Kontos CD, Donatucci CF, Annex BH. Cholesterol feeding reduces vascular endothelial growth factor signaling in rabbit corporal tissues. J Sex Med  2005; 2(5): 634-40.
 [http://dx.doi.org/10.1111/j.1743-6109.2005.00111.x] [PMID: 16422820]

[219]
Zhang Y, Yang J, Zhuan L, Zang G, Wang T, Liu J. Transplantation of adipose-derived stem cells overexpressing inducible nitric oxide synthase ameliorates diabetes mellitus-induced erectile dysfunction in rats. PeerJ  2019; 7: e7507.
 [http://dx.doi.org/10.7717/peerj.7507] [PMID: 31423366]

[220]
Wang J, Cao X, Deng S, et al. Effect of liver cirrhosis on erectile function in rats: A study combining bioinformatics analysis and experimental research. Andrologia  2022; 54(3): e14352.
 [http://dx.doi.org/10.1111/and.14352] [PMID: 34921688]

[221]
Zhao S, Liu L, Kang R. Shengjing capsule improves erectile function through regulation of nitric oxide-induced relaxation in corpus cavernosum smooth muscle in a castrated rat model. Urology  2016; 9154: 243.e7-243.e12.
 [http://dx.doi.org/10.1016/j.urology.2016.02.021]

[222]
Zhang Y, Huang C, Liu S, et al. Effects of quercetin on intracavernous pressure and expression of nitrogen synthase isoforms in arterial erectile dysfunction rat model. Int J Clin Exp Med  2015; 8(5): 7599-605.
 [PMID: 26221305]

[223]
Liu WJ, Xin ZC, Xin H, Yuan YM, Tian L, Guo YL. Effects of icariin on erectile function and expression of nitric oxide synthase isoforms in castrated rats. Asian J Androl  2005; 7(4): 381-8.
 [http://dx.doi.org/10.1111/j.1745-7262.2005.00066.x] [PMID: 16281085]

[224]
Ismail EA, Younis SE, Ismail IY, El-Wazir YM, El-Sakka AI. Early administration of phosphodiesterase 5 inhibitors after induction of diabetes in a rat model may prevent erectile dysfunction. Andrology  2020; 8(1): 241-8.
 [http://dx.doi.org/10.1111/andr.12668] [PMID: 31250549]

[225]
Ferrini MG, Rivera S, Moon J, Vernet D, Rajfer J, Gonzalez-Cadavid NF. The genetic inactivation of inducible nitric oxide synthase (iNOS) intensifies fibrosis and oxidative stress in the penile corpora cavernosa in type 1 diabetes. J Sex Med  2010; 7(9): 3033-44.
 [http://dx.doi.org/10.1111/j.1743-6109.2010.01884.x] [PMID: 20626593]

[226]
Davila HH, Magee TR, Vernet D, Rajfer J, Gonzalez-Cadavid NF. Gene transfer of inducible nitric oxide synthase complementary DNA regresses the fibrotic plaque in an animal model of Peyronie’s disease. Biol Reprod  2004; 71(5): 1568-77.
 [http://dx.doi.org/10.1095/biolreprod.104.030833] [PMID: 15240426]

[227]
Wessells H, Teal TH, Luttrell IP, Sullivan CJ. Effect of endothelial cell-based iNOS gene transfer on cavernosal eNOS expression and mouse erectile responses. Int J Impot Res  2006; 18(5): 438-45.
 [http://dx.doi.org/10.1038/sj.ijir.3901464] [PMID: 16554854]

[228]
Liu L, Wang X, Liu K, et al. Inhibition of inducible nitric oxide synthase improved erectile dysfunction in rats with type 1 diabetes. Andrologia  2021; 53(8): e14138.
 [http://dx.doi.org/10.1111/and.14138] [PMID: 34137064]

[229]
Kovanecz I, Rambhatla A, Ferrini M, et al. Long-term continuous sildenafil treatment ameliorates corporal veno-occlusive dysfunction (CVOD) induced by cavernosal nerve resection in rats. Int J Impot Res  2008; 20(2): 202-12.
 [http://dx.doi.org/10.1038/sj.ijir.3901612] [PMID: 17882231]

[230]
Chen B, Lu Y, Chen Y, Cheng J. The role of Nrf2 in oxidative stress-induced endothelial injuries. J Endocrinol  2015; 225(3): R83-99.
 [http://dx.doi.org/10.1530/JOE-14-0662] [PMID: 25918130]

[231]
Kim CY, Kang B, Hong J, Choi HS. Parthenolide inhibits lipid accumulation via activation of Nrf2/Keap1 signaling during adipocyte differentiation. Food Sci Biotechnol  2020; 29(3): 431-40.
 [http://dx.doi.org/10.1007/s10068-019-00672-y] [PMID: 32257527]

[232]
Luo Z, Aslam S, Welch WJ, Wilcox CS. Activation of nuclear factor erythroid 2-related factor 2 coordinates dimethylarginine dimethylaminohydrolase/PPAR-γ/endothelial nitric oxide synthase pathways that enhance nitric oxide generation in human glomerular endothelial cells. Hypertension  2015; 65(4): 896-902.
 [http://dx.doi.org/10.1161/HYPERTENSIONAHA.114.04760] [PMID: 25691623]

[233]
Wang Y, Wang Y, Cong R, et al. Restoration of erectile function by suppression of corporal apoptosis and oxidative stress with losartan in aged rats with erectile dysfunction. Andrology  2020; 8(3): 769-79.
 [http://dx.doi.org/10.1111/andr.12757] [PMID: 31968148]

[234]
Zhong L, Ding W, Zeng Q, et al. Sodium tanshinone IIA sulfonate attenuates erectile dysfunction in rats with hyperlipidemia. Oxid Med Cell Longev  2020; 2020: 7286958.
 [PMID: 32215177]

[235]
Hu LL, Zhang KQ, Tian T, Zhang H, Fu Q. Probucol improves erectile function via Activation of Nrf2 and coordinates the HO-1/DDAH/PPAR-γ/eNOS pathways in streptozotocin-induced diabetic rats. Biochem Biophys Res Commun  2018; 507(1-4): 9-14.
 [http://dx.doi.org/10.1016/j.bbrc.2018.10.036] [PMID: 30454888]

[236]
Besong EE, Akhigbe TM, Ashonibare PJ, et al. Zinc improves sexual performance and erectile function by preventing penile oxidative injury and upregulating circulating testosterone in lead-exposed rats. Redox Rep  2023; 28(1): 2225675.
 [http://dx.doi.org/10.1080/13510002.2023.2225675] [PMID: 37345699]

[237]
Wang H, Zhang K, Ruan Z, et al. Probucol enhances the therapeutic efficiency of mesenchymal stem cells in the treatment of erectile dysfunction in diabetic rats by prolonging their survival time via Nrf2 pathway. Stem Cell Res Ther  2020; 11(1): 302.
 [http://dx.doi.org/10.1186/s13287-020-01788-3] [PMID: 32693824]

[238]
Jeon SH, Bae WJ, Zhu GQ, et al. Combined treatment with extracorporeal shockwaves therapy and an herbal formulation for activation of penile progenitor cells and antioxidant activity in diabetic erectile dysfunction. Transl Androl Urol  2020; 9(2): 416-27.
 [http://dx.doi.org/10.21037/tau.2020.01.23] [PMID: 32420147]

[239]
Angulo J, El Assar M, Sevilleja-Ortiz A, et al. Short-term pharmacological activation of Nrf2 ameliorates vascular dysfunction in aged rats and in pathological human vasculature. A potential target for therapeutic intervention. Redox Biol  2019; 26: 101271.
 [http://dx.doi.org/10.1016/j.redox.2019.101271] [PMID: 31302408]

[240]
Bedard K, Krause KH. The NOX family of ROS-generating NADPH oxidases: Physiology and pathophysiology. Physiol Rev  2007; 87(1): 245-313.
 [http://dx.doi.org/10.1152/physrev.00044.2005] [PMID: 17237347]

[241]
Fraga-Silva RA, Costa-Fraga FP, Savergnini SQ, et al. An oral formulation of angiotensin-(1-7) reverses corpus cavernosum damages induced by hypercholesterolemia. J Sex Med  2013; 10(10): 2430-42.
 [http://dx.doi.org/10.1111/jsm.12262] [PMID: 23890028]

[242]
Musicki B, Hannan JL, Lagoda G, Bivalacqua TJ, Burnett AL. Mechanistic link between erectile dysfunction and systemic endothelial dysfunction in type 2 diabetic rats. Andrology  2016; 4(5): 977-83.
 [http://dx.doi.org/10.1111/andr.12218] [PMID: 27153512]

[243]
Li M, Zhuan L, Wang T, et al. Apocynin improves erectile function in diabetic rats through regulation of NADPH oxidase expression. J Sex Med  2012; 9(12): 3041-50.
 [http://dx.doi.org/10.1111/j.1743-6109.2012.02960.x] [PMID: 23088159]

[244]
Xu M, Tang YQ, Dai DZ, et al. Comparison of sildenafil with strontium fructose diphosphate in improving erectile dysfunction against upregulated cavernosal NADPH oxidase, protein kinase C ε, and endothelin system in diabetic rats. J Pharm Pharmacol  2012; 64(2): 244-51.
 [http://dx.doi.org/10.1111/j.2042-7158.2011.01390.x] [PMID: 22221100]

[245]
He W, Liu J, Liu D, et al. Alterations in the phosphodiesterase type 5 pathway and oxidative stress correlate with erectile function in spontaneously hypertensive rats. J Cell Mol Med  2020; 24(24): 14280-92.
 [http://dx.doi.org/10.1111/jcmm.16045] [PMID: 33118708]

[246]
Long H, Jiang J, Xia J, Jiang R. Icariin improves SHR erectile function via inhibiting eNOS uncoupling. Andrologia  2018; 50(9): e13084.
 [http://dx.doi.org/10.1111/and.13084] [PMID: 29968380]

[247]
Yang J, Wang T, Yang J, et al. S ‐allyl cysteine restores erectile function through inhibition of reactive oxygen species generation in diabetic rats. Andrology  2013; 1(3): 487-94.
 [http://dx.doi.org/10.1111/j.2047-2927.2012.00060.x] [PMID: 23427186]

[248]
Jiang S, Cai Q, Gao Y, et al. Trigonella foenum-graecum L. and Psoralea corylifolia L. Improve Erectile Dysfunction in Streptozotocin-Induced Diabetic Rats through Suppression of Oxidative Stress. Evid Based Complement Alternat Med  2022; 2022: 1-11.
 [http://dx.doi.org/10.1155/2022/4187359] [PMID: 35707467]

[249]
Dalaklioglu S, Tasatargil A, Kuscu N, et al. Protective effect of exendin-4 treatment on erectile dysfunction induced by chronic methylglyoxal administration in rats. Peptides  2018; 106: 1-8.
 [http://dx.doi.org/10.1016/j.peptides.2018.05.005] [PMID: 29792899]

[250]
Yuan P, Ma D, Gao X, et al. Liraglutide Ameliorates Erectile Dysfunction via Regulating Oxidative Stress, the RhoA/ROCK Pathway and Autophagy in Diabetes Mellitus. Front Pharmacol  2020; 11: 1257.
 [http://dx.doi.org/10.3389/fphar.2020.01257] [PMID: 32903510]

[251]
Chiangsaen P, Maneesai P, Kukongviriyapan U, et al. Tangeretin ameliorates erectile and testicular dysfunction in a rat model of hypertension. Reprod Toxicol  2020; 96: 1-10.
 [http://dx.doi.org/10.1016/j.reprotox.2020.05.012] [PMID: 32479886]

[252]
La Favor JD, Pierre CJ, Bivalacqua TJ, Burnett AL. Rapamycin suppresses penile NADPH oxidase activity to preserve erectile function in mice fed a western diet. Biomedicines  2021; 10(1): 68.
 [http://dx.doi.org/10.3390/biomedicines10010068] [PMID: 35052748]

[253]
Zhou B, Chen Y, Yuan H, et al. NOX1/4 inhibitor GKT-137831 improves erectile function in diabetic rats by ROS reduction and endothelial nitric oxide synthase reconstitution. J Sex Med  2021; 18(12): 1970-83.
 [http://dx.doi.org/10.1016/j.jsxm.2021.09.007] [PMID: 34649814]

[254]
Xiong W, Kong X, Jiang J, Yang Z, Jiang R. Low androgen status inhibits erectile function by inducing eNOS uncoupling in rat corpus cavernosum. Andrology  2020; 8(6): 1875-83.
 [http://dx.doi.org/10.1111/andr.12844] [PMID: 32594586]

[255]
Li R, Meng X, Zhang Y, et al. Testosterone improves erectile function through inhibition of reactive oxygen species generation in castrated rats. PeerJ  2016; 4: e2000.
 [http://dx.doi.org/10.7717/peerj.2000] [PMID: 27168996]

[256]
Kataoka T, Hotta Y, Maeda Y, Kimura K. Testosterone deficiency causes endothelial dysfunction via elevation of asymmetric dimethylarginine and oxidative stress in castrated rats. J Sex Med  2017; 14(12): 1540-8.
 [http://dx.doi.org/10.1016/j.jsxm.2017.11.001] [PMID: 29198509]

[257]
Tang Z, Song J, Yu Z, et al. Melatonin Treatment Ameliorates Hyperhomocysteinemia-Induced Impairment of Erectile Function in a Rat Model. J Sex Med  2019; 16(10): 1506-17.
 [http://dx.doi.org/10.1016/j.jsxm.2019.07.003] [PMID: 31439521]

[258]
Iacopucci APM, da Silva Pereira P, Pereira DA, et al. Intravascular hemolysis leads to exaggerated corpus cavernosum relaxation: Implication for priapism in sickle cell disease. FASEB J  2022; 36(10): e22535.
 [http://dx.doi.org/10.1096/fj.202200867R] [PMID: 36070139]

[259]
Kimura M, Rabbani ZN, Zodda AR, et al. Role of oxidative stress in a rat model of radiation-induced erectile dysfunction. J Sex Med  2012; 9(6): 1535-49.
 [http://dx.doi.org/10.1111/j.1743-6109.2012.02716.x] [PMID: 22489731]

[260]
Karakus S, Musicki B, La Favor JD, Burnett AL. cAMP ‐dependent post‐translational modification of neuronal nitric oxide synthase neuroprotects penile erection in rats. BJU Int  2017; 120(6): 861-72.
 [http://dx.doi.org/10.1111/bju.13981] [PMID: 28782252]

[261]
Pereira AS, Gouveia AM, Tomada N, Rodrigues AR, Neves D. Cumulative effect of cardiovascular risk factors on regulation of AMPK/SIRT1-PGC-1 α-SIRT3 pathway in the human erectile tissue. Oxid Med Cell Longev  2020; 2020: 1-10.
 [http://dx.doi.org/10.1155/2020/1525949] [PMID: 32377289]

[262]
Klionsky DJ, Emr SD. Autophagy as a regulated pathway of cellular degradation. Science  2000; 290(5497): 1717-21.
 [http://dx.doi.org/10.1126/science.290.5497.1717] [PMID: 11099404]

[263]
Li M, Zhu X, Zhao B, et al. Adrenomedullin alleviates the pyroptosis of Leydig cells by promoting autophagy via the ROS–AMPK–mTOR axis. Cell Death Dis  2019; 10(7): 489.
 [http://dx.doi.org/10.1038/s41419-019-1728-5] [PMID: 31222000]

[264]
Fryer LG, Hajduch E, Rencurel F, et al. Activation of glucose transport by AMP-activated protein kinase via stimulation of nitric oxide synthase. Diabetes  2000; 49(12): 1978-85.
 [http://dx.doi.org/10.2337/diabetes.49.12.1978] [PMID: 11117997]

[265]
Chen Z, Peng IC, Sun W, et al. AMP-activated protein kinase functionally phosphorylates endothelial nitric oxide synthase Ser633. Circ Res  2009; 104(4): 496-505.
 [http://dx.doi.org/10.1161/CIRCRESAHA.108.187567] [PMID: 19131647]

[266]
Chen ZP, Mitchelhill KI, Michell BJ, et al. AMP‐activated protein kinase phosphorylation of endothelial NO synthase. FEBS Lett  1999; 443(3): 285-9.
 [http://dx.doi.org/10.1016/S0014-5793(98)01705-0] [PMID: 10025949]

[267]
Ding F, Shan C, Li H, et al. Simvastatin alleviated diabetes mellitus‐induced erectile dysfunction in rats by enhancing AMPK pathway‐induced autophagy. Andrology  2020; 8(3): 780-92.
 [http://dx.doi.org/10.1111/andr.12758] [PMID: 31955524]

[268]
Lin H, Wang T, Ruan Y, et al. Rapamycin supplementation may ameliorate erectile function in rats with streptozotocin-induced type 1 diabetes by inducing autophagy and inhibiting apoptosis, endothelial dysfunction, and corporal fibrosis. J Sex Med  2018; 15(9): 1246-59.
 [http://dx.doi.org/10.1016/j.jsxm.2018.07.013] [PMID: 30224017]

[269]
Labazi H, Wynne BM, Tostes R, Webb RC. Metformin treatment improves erectile function in an angiotensin II model of erectile dysfunction. J Sex Med  2013; 10(9): 2154-64.
 [http://dx.doi.org/10.1111/jsm.12245] [PMID: 23889981]

[270]
Kim YW, Park SY, Kim JY, et al. Metformin restores the penile expression of nitric oxide synthase in high-fat-fed obese rats. J Androl  2007; 28(4): 555-60.
 [http://dx.doi.org/10.2164/jandrol.106.001602] [PMID: 17314235]

[271]
Klionsky DJ, Petroni G, Amaravadi RK, et al. Autophagy in major human diseases. EMBO J  2021; 40(19): e108863.
 [http://dx.doi.org/10.15252/embj.2021108863] [PMID: 34459017]

[272]
Eid AA, Ford BM, Bhandary B, et al. Mammalian target of rapamycin regulates Nox4-mediated podocyte depletion in diabetic renal injury. Diabetes  2013; 62(8): 2935-47.
 [http://dx.doi.org/10.2337/db12-1504] [PMID: 23557706]

[273]
Mathew R, Karp CM, Beaudoin B, et al. Autophagy suppresses tumorigenesis through elimination of p62. Cell  2009; 137(6): 1062-75.
 [http://dx.doi.org/10.1016/j.cell.2009.03.048] [PMID: 19524509]

[274]
Wrighton KH. Kinase crosstalk through beclin 1. Nat Rev Mol Cell Biol  2013; 14(7): 402-3.
 [http://dx.doi.org/10.1038/nrm3608] [PMID: 23756621]

[275]
Banduseela VC, Chen YW, Kultima HG, et al. Impaired autophagy, chaperone expression, and protein synthesis in response to critical illness interventions in porcine skeletal muscle. Physiol Genomics  2013; 45(12): 477-86.
 [http://dx.doi.org/10.1152/physiolgenomics.00141.2012] [PMID: 23572537]

[276]
Xiao L, Wang YC, Li WS, Du Y. The role of mTOR and phospho-p70S6K in pathogenesis and progression of gastric carcinomas: An immunohistochemical study on tissue microarray. J Exp Clin Cancer Res  2009; 28(1): 152.
 [http://dx.doi.org/10.1186/1756-9966-28-152] [PMID: 20003385]

[277]
Zhang J, Li S, Li S, et al. Effect of icariside II and metformin on penile erectile function, glucose metabolism, reaction oxygen species, superoxide dismutase, and mitochondrial autophagy in type 2 diabetic rats with erectile dysfunction. Transl Androl Urol  2020; 9(2): 355-66.
 [http://dx.doi.org/10.21037/tau.2020.02.07] [PMID: 32420141]

[278]
Li R, Cui K, Wang T, et al. Hyperlipidemia impairs erectile function in rats by causing cavernosal fibrosis. Andrologia  2017; 49(7): e12693.
 [http://dx.doi.org/10.1111/and.12693] [PMID: 27619893]

[279]
Wang XJ, Xu TY, Xia LL, et al. Castration impairs erectile organ structure and function by inhibiting autophagy and promoting apoptosis of corpus cavernosum smooth muscle cells in rats. Int Urol Nephrol  2015; 47(7): 1105-15.
 [http://dx.doi.org/10.1007/s11255-015-1011-3] [PMID: 25997594]

[280]
Yuan J-H, Wu C-J, Fu F-D, et al. Vacuum therapy ameliorates erectile dysfunction in bilateral cavernous nerve crush rats by inhibiting apoptosis and activating autophagy. Asian J Androl  2021; 23(3): 273-80.
 [http://dx.doi.org/10.4103/aja.aja_79_20] [PMID: 33473012]

[281]
Zhang C, Luo D, Li T, et al. Transplantation of human urine-derived stem cells ameliorates erectile function and cavernosal endothelial function by promoting autophagy of corpus cavernosal endothelial cells in diabetic erectile dysfunction rats. Stem Cells Int  2019; 2019: 1-13.
 [http://dx.doi.org/10.1155/2019/2168709] [PMID: 31582984]

[282]
Tang Z, Cui K, Luan Y, et al. Human tissue kallikrein 1 ameliorates erectile function via modulation of macroautophagy in aged transgenic rats. Andrology  2018; 6(5): 766-74.
 [http://dx.doi.org/10.1111/andr.12512] [PMID: 29939496]

[283]
Zhang J, Wu XJ, Zhuo DX, et al. Effect of tankyrase 1 on autophagy in the corpus cavernosum smooth muscle cells from ageing rats with erectile dysfunction and its potential mechanism. Asian J Androl  2010; 12(5): 744-52.
 [http://dx.doi.org/10.1038/aja.2010.44] [PMID: 20657601]

[284]
Lagoda G, Sezen SF, Burnett AL. FK506 and rapamycin neuroprotect erection and involve different immunophilins in a rat model of cavernous nerve injury. J Sex Med  2009; 6(7): 1914-23.
 [http://dx.doi.org/10.1111/j.1743-6109.2009.01293.x] [PMID: 19453873]

[285]
Ma KH, Zhang YW, Pan LR, et al. Effects of rapamycin on glucose-induced autophagy and apoptosis of corpus cavernosum smooth muscle cells in SD rats]. Zhonghua Nan Ke Xue  2020; 26(11): 969-78.
 [PMID: 34898065]

[286]
Lee JW, Bae SH, Jeong JW, Kim SH, Kim KW. Hypoxia-inducible factor (HIF-1)α: Its protein stability and biological functions. Exp Mol Med  2004; 36(1): 1-12.
 [http://dx.doi.org/10.1038/emm.2004.1] [PMID: 15031665]

[287]
Lv B, Zhao J, Yang F, et al. Phenotypic transition of corpus cavernosum smooth muscle cells subjected to hypoxia. Cell Tissue Res  2014; 357(3): 823-33.
 [http://dx.doi.org/10.1007/s00441-014-1902-0] [PMID: 24913687]

[288]
Zhang X, Zhao J, Zhao F, et al. The protective effect of salidroside on hypoxia-induced corpus cavernosum smooth muscle cell phenotypic transformation. Evid Based Complement Alternat Med  2017; 2017: 1-11.
 [http://dx.doi.org/10.1155/2017/3530281] [PMID: 28798798]

[289]
Lee M, Ryu JK, Piao S, et al. Efficient gene expression system using the RTP801 promoter in the corpus cavernosum of high-cholesterol diet-induced erectile dysfunction rats for gene therapy. J Sex Med  2008; 5(6): 1355-64.
 [http://dx.doi.org/10.1111/j.1743-6109.2008.00771.x] [PMID: 18312285]

[290]
Seftel AD, Maclennan GT, Chen ZJ, et al. Loss of TGFbeta, apoptosis, and Bcl-2 in erectile dysfunction and upregulation of p53 and HIF-1 alpha in diabetes-associated erectile dysfunction. Mol Urol  1999; 3(2): 103-7.
 [PMID: 10851311]

[291]
Bryan BA, Dennstedt E, Mitchell DC, et al. RhoA/ROCK signaling is essential for multiple aspects of VEGF‐mediated angiogenesis. FASEB J  2010; 24(9): 3186-95.
 [http://dx.doi.org/10.1096/fj.09-145102] [PMID: 20400538]

[292]
Bivalacqua TJ, Ross AE, Strong TD. Attenuated RhoA/Rho-kinase signaling in penis of transgenic sickle cell mice. Urology  2010; 76(2): 510.

[293]
Chitaley K, Wingard CJ, Clinton Webb R, et al. Antagonism of Rho-kinase stimulates rat penile erection via a nitric oxide-independent pathway. Nat Med  2001; 7(1): 119-22.
 [http://dx.doi.org/10.1038/83258] [PMID: 11135626]

[294]
Chang S, Hypolite JA, Changolkar A, Wein AJ, Chacko S, DiSanto ME. Increased contractility of diabetic rabbit corpora smooth muscle in response to endothelin is mediated via Rho-kinase β. Int J Impot Res  2003; 15(1): 53-62.
 [http://dx.doi.org/10.1038/sj.ijir.3900947] [PMID: 12605241]

[295]
Bivalacqua TJ, Champion HC, Usta MF, et al. RhoA/Rho-kinase suppresses endothelial nitric oxide synthase in the penis: A mechanism for diabetes-associated erectile dysfunction. Proc Natl Acad Sci USA  2004; 101(24): 9121-6.
 [http://dx.doi.org/10.1073/pnas.0400520101] [PMID: 15184671]

[296]
Gao BH, Zhao ST, Meng FW, Shi BK, Liu YQ, Xu ZS. Y-27632 improves the erectile dysfunction with ageing in SD rats through adjusting the imbalance between nNo and the Rho-kinase pathways. Andrologia  2007; 39(4): 146-50.
 [http://dx.doi.org/10.1111/j.1439-0272.2007.00782.x] [PMID: 17683464]

[297]
Leite R, Giachini FR, Carneiro FS, Nunes KP, Tostes RC, Webb RC. Targets for the treatment of erectile dysfunction: Is NO/cGMP still the answer? Recent Pat Cardiovasc Drug Discov  2007; 2(2): 119-32.
 [http://dx.doi.org/10.2174/157489007780832579] [PMID: 18221110]

[298]
Priviero FBM, Jin LM, Ying Z, Teixeira CE, Webb RC. Up-regulation of the RhoA/Rho-kinase signaling pathway in corpus cavernosum from endothelial nitric-oxide synthase (NOS), but not neuronal NOS, null mice. J Pharmacol Exp Ther  2010; 333(1): 184-92.
 [http://dx.doi.org/10.1124/jpet.109.160606] [PMID: 20093396]

[299]
Rajasekaran M, White S, Baquir A, Wilkes N. Rho-kinase inhibition improves erectile function in aging male Brown-Norway rats. J Androl  2005; 26(2): 182-8.
 [http://dx.doi.org/10.1002/j.1939-4640.2005.tb01084.x] [PMID: 15713824]

[300]
Jin L, Liu T, Lagoda GA, Champion HC, Bivalacqua TJ, Burnett AL. Elevated RhoA/Rho‐kinase activity in the aged rat penis: Mechanism for age‐associated erectile dysfunction. FASEB J  2006; 20(3): 536-8.
 [http://dx.doi.org/10.1096/fj.05-4232fje] [PMID: 16396994]

[301]
Chitaley K, Webb RC, Dorrance AM, Mills TM. Decreased penile erection in DOCA-salt and stroke prone-spontaneously hypertensive rats. Int J Impot Res  2001; 13(S5) (Suppl. 5): S16-20.
 [http://dx.doi.org/10.1038/sj.ijir.3900773] [PMID: 11781742]

[302]
Higashi M, Shimokawa H, Hattori T, et al. Long-term inhibition of Rho-kinase suppresses angiotensin II-induced cardiovascular hypertrophy in rats in vivo: Effect on endothelial NAD(P)H oxidase system. Circ Res  2003; 93(8): 767-75.
 [http://dx.doi.org/10.1161/01.RES.0000096650.91688.28] [PMID: 14500337]

[303]
Park K, Kim SW, Rhu KS, Paick JS. Chronic administration of an oral Rho kinase inhibitor prevents the development of vasculogenic erectile dysfunction in a rat model. J Sex Med  2006; 3(6): 996-1003.
 [http://dx.doi.org/10.1111/j.1743-6109.2006.00327.x] [PMID: 17100932]

[304]
Qinyu Zeng, Shuhua He, Fengzhi Chen, et al. Administration of H2S improves erectile dysfunction by inhibiting phenotypic modulation of corpus cavernosum smooth muscle in bilateral cavernous nerve injury rats. Nitric Oxide  2021; 107: 1-10.
 [http://dx.doi.org/10.1016/j.niox.2020.11.003] [PMID: 33246103]

[305]
Morelli A, Chavalmane AK, Filippi S, et al. Atorvastatin ameliorates sildenafil-induced penile erections in experimental diabetes by inhibiting diabetes-induced RhoA/Rho-kinase signaling hyperactivation. J Sex Med  2009; 6(1): 91-106.
 [http://dx.doi.org/10.1111/j.1743-6109.2008.01057.x] [PMID: 19170840]

[306]
Toque HA, Nunes KP, Yao L, et al. Activated Rho kinase mediates diabetes-induced elevation of vascular arginase activation and contributes to impaired corpora cavernosa relaxation: Possible involvement of p38 MAPK activation. J Sex Med  2013; 10(6): 1502-15.
 [http://dx.doi.org/10.1111/jsm.12134] [PMID: 23566117]

[307]
Pereira PS, Pereira DA, Calmasini FB, et al. Haptoglobin treatment contributes to regulating nitric oxide signal and reduces oxidative stress in the penis: A preventive treatment for priapism in sickle cell disease. Front Physiol  2022; 13: 961534.
 [http://dx.doi.org/10.3389/fphys.2022.961534] [PMID: 36176769]

[308]
Wynne BM, Chiao CW, Webb RC. Vascular smooth muscle cell signaling mechanisms for contraction to angiotensin II and endothelin-1. J Am Soc Hypertens  2009; 3(2): 84-95.
 [http://dx.doi.org/10.1016/j.jash.2008.09.002] [PMID: 20161229]

[309]
Kifor I, Williams GH, Vickers MA, Sullivan MP, Jodbert P, Dluhy RG. Tissue angiotensin II as a modulator of erectile function. I. Angiotensin peptide content, secretion and effects in the corpus cavernosum. J Urol  1997; 157(5): 1920-5.
 [http://dx.doi.org/10.1016/S0022-5347(01)64901-2] [PMID: 9112563]

[310]
Jin L, Lagoda G, Leite R, Webb RC, Burnett AL. NADPH oxidase activation: A mechanism of hypertension-associated erectile dysfunction. J Sex Med  2008; 5(3): 544-51.
 [http://dx.doi.org/10.1111/j.1743-6109.2007.00733.x] [PMID: 18208505]

[311]
Becker AJ, Ückert S, Stief CG, et al. Plasma levels of angiotensin II during different penile conditions in the cavernous and systemic blood of healthy men and patients with erectile dysfunction. Urology  2001; 58(5): 805-10.
 [http://dx.doi.org/10.1016/S0090-4295(01)01312-7] [PMID: 11711372]

[312]
El Melegy NT, Ali MEM, Awad EMA. Plasma levels of endothelin‐1, angiotensin II, nitric oxide and prostaglandin E 2 in the venous and cavernosal blood of patients with erectile dysfunction. BJU Int  2005; 96(7): 1079-86.
 [http://dx.doi.org/10.1111/j.1464-410X.2005.05780.x] [PMID: 16225532]

[313]
Li WJ, Xu M, Gu M, et al. Losartan preserves erectile function by suppression of apoptosis and fibrosis of corpus cavernosum and corporal veno-occlusive dysfunction in diabetic rats. Cell Physiol Biochem  2017; 42(1): 333-45.
 [http://dx.doi.org/10.1159/000477388] [PMID: 28535536]

[314]
Zhang Y, Jia L, Zhang Y, Ji W, Li H, Angiotensin II. Angiotensin II silencing alleviates erectile dysfunction through down-regulating the Rhoa/Rho kinase signaling pathway in rats with diabetes mellitus. Cell Physiol Biochem  2018; 45(1): 419-27.
 [http://dx.doi.org/10.1159/000486919] [PMID: 29402797]

[315]
Bivalacqua TJ, Usta MF, Champion HC, Kadowitz PJ, Hellstrom WJG. Endothelial dysfunction in erectile dysfunction: Role of the endothelium in erectile physiology and disease. J Androl  2003; 24(S6) (Suppl.): S17-37.
 [http://dx.doi.org/10.1002/j.1939-4640.2003.tb02743.x] [PMID: 14581492]

[316]
Bouallegue A, Bou Daou G, Srivastava A. Endothelin-1-induced signaling pathways in vascular smooth muscle cells. Curr Vasc Pharmacol  2007; 5(1): 45-52.
 [http://dx.doi.org/10.2174/157016107779317161] [PMID: 17266612]

[317]
Bocchio M, Desideri G, Scarpelli P, et al. Endothelial cell activation in men with erectile dysfunction without cardiovascular risk factors and overt vascular damage. J Urol  2004; 171(4): 1601-4.
 [http://dx.doi.org/10.1097/01.ju.0000116325.06572.85] [PMID: 15017230]

[318]
Francavilla S, Properzi G, Bellini C, Marino G, Ferri C, Santucci A. Endothelin-1 in diabetic and nondiabetic men with erectile dysfunction. J Urol  1997; 158(5): 1770-4.
 [http://dx.doi.org/10.1016/S0022-5347(01)64125-9] [PMID: 9334598]

[319]
Hamed EA, Meki ARMA, Gaafar AAA, Hamed SA. Role of some vasoactive mediators in patients with erectile dysfunction: Their relationship with angiotensin-converting enzyme and growth hormone. Int J Impot Res  2003; 15(6): 418-25.
 [http://dx.doi.org/10.1038/sj.ijir.3901059] [PMID: 14671660]

[320]
Mills TM, Chitaley K, Wingard CJ, Lewis RW, Webb RC. Effect of Rho-kinase inhibition on vasoconstriction in the penile circulation. J Appl Physiol (1985)  2001; 91(3): 1269-73.

[321]
Wang H, Eto M, Steers WD, Somlyo AP, Somlyo AV. RhoA-mediated Ca2+ sensitization in erectile function. J Biol Chem  2002; 277(34): 30614-21.
 [http://dx.doi.org/10.1074/jbc.M204262200] [PMID: 12060659]

[322]
Ari G, Vardi Y, Hoffman A, Finberg JPM. Possible role for endothelins in penile erection. Eur J Pharmacol  1996; 307(1): 69-74.
 [http://dx.doi.org/10.1016/0014-2999(96)00172-0] [PMID: 8831106]

[323]
Wingard CJ, Husain S, Williams J, James S. RhoA-Rho kinase mediates synergistic ET-1 and phenylephrine contraction of rat corpus cavernosum. Am J Physiol Regul Integr Comp Physiol  2003; 285(5): R1145-52.
 [http://dx.doi.org/10.1152/ajpregu.00329.2003] [PMID: 12893655]

[324]
Carneiro FS, Nunes KP, Giachini FRC, et al. Activation of the ET-1/ETA pathway contributes to erectile dysfunction associated with mineralocorticoid hypertension. J Sex Med  2008; 5(12): 2793-807.
 [http://dx.doi.org/10.1111/j.1743-6109.2008.01009.x] [PMID: 18823320]

[325]
Kitada M, Ogura Y, Monno I, Koya D. Sirtuins and Type 2 Diabetes: Role in Inflammation, Oxidative Stress, and Mitochondrial Function. Front Endocrinol (Lausanne)  2019; 10: 187.
 [http://dx.doi.org/10.3389/fendo.2019.00187] [PMID: 30972029]

[326]
Sahan A, Akbal C, Tavukcu HH, et al. Melatonin prevents deterioration of erectile function in streptozotocin‐induced diabetic rats via sirtuin‐1 expression. Andrologia  2020; 52(9): e13639.
 [http://dx.doi.org/10.1111/and.13639] [PMID: 32478903]

[327]
Sener TE, Tavukcu HH, Atasoy BM, et al. Resveratrol treatment may preserve the erectile function after radiotherapy by restoring antioxidant defence mechanisms, SIRT1 and NOS protein expressions. Int J Impot Res  2018; 30(4): 179-88.
 [http://dx.doi.org/10.1038/s41443-018-0042-6] [PMID: 29973698]

[328]
Yu W, Xu ZP, Che XY, Chen Y, Dai YT. Aging-related change of erectile function and the expression of SIRT1]. Zhonghua Nan Ke Xue  2016; 22(12): 1077-82.
 [PMID: 29282911]

[329]
Zhang A-X, Dai Y-T, Pan F, et al. MicroRNA-200a is up-regulated in aged rats with erectile dysfunction and could attenuate endothelial function via SIRT1 inhibition. Asian J Androl  2016; 18(1): 74-9.
 [http://dx.doi.org/10.4103/1008-682X.154991] [PMID: 25966629]

[330]
Tomada I, Negrão R, Almeida H, Neves D. Long-term high-fat consumption leads to downregulation of Akt phosphorylation of eNOS at Ser1177 and upregulation of Sirtuin-1 expression in rat cavernous tissue. Age (Omaha)  2014; 36(2): 597-611.
 [http://dx.doi.org/10.1007/s11357-013-9591-2] [PMID: 24105250]

[331]
Pereira C, Severo M, Rafael L, Martins M, Neves D. Effects of natural mineral-rich water consumption on the expression of sirtuin 1 and angiogenic factors in the erectile tissue of rats with fructose-induced metabolic syndrome. Asian J Androl  2014; 16(4): 631-8.
 [http://dx.doi.org/10.4103/1008-682X.122869] [PMID: 24625878]

[332]
Fukuhara S, Tsujimura A, Okuda H, et al. Vardenafil and resveratrol synergistically enhance the nitric oxide/cyclic guanosine monophosphate pathway in corpus cavernosal smooth muscle cells and its therapeutic potential for erectile dysfunction in the streptozotocin-induced diabetic rat: Preliminary findings. J Sex Med  2011; 8(4): 1061-71.
 [http://dx.doi.org/10.1111/j.1743-6109.2010.02193.x] [PMID: 21269399]

[333]
Xu Z-P, Yu W, Wang J, et al. Modulation of SIRT1 expression improves erectile function in aged rats. Asian J Androl  2022; 24(6): 666-70.
 [http://dx.doi.org/10.4103/aja202199] [PMID: 35229761]

[334]
Yu W, Wan Z, Qiu XF, Chen Y, Dai YT. Resveratrol, an activator of SIRT1, restores erectile function in streptozotocin-induced diabetic rats. Asian J Androl  2013; 15(5): 646-51.
 [http://dx.doi.org/10.1038/aja.2013.60] [PMID: 23792339]

[335]
Tomada I, Tomada N, Almeida H, Neves D. Androgen depletion in humans leads to cavernous tissue reorganization and upregulation of Sirt1–eNOS axis. Age (Omaha)  2013; 35(1): 35-47.
 [http://dx.doi.org/10.1007/s11357-011-9328-z] [PMID: 22052036]

[336]
Zhao W, Zhang J, Lu Y, Wang R. The vasorelaxant effect of H2S as a novel endogenous gaseous KATP channel opener. EMBO J  2001; 20(21): 6008-16.
 [http://dx.doi.org/10.1093/emboj/20.21.6008] [PMID: 11689441]

[337]
d’Emmanuele di Villa Bianca R, Sorrentino R, Maffia P, et al. Hydrogen sulfide as a mediator of human corpus cavernosum smooth-muscle relaxation. Proc Natl Acad Sci USA  2009; 106(11): 4513-8.
 [http://dx.doi.org/10.1073/pnas.0807974105] [PMID: 19255435]

[338]
Mitidieri E, Tramontano T, Gurgone D, et al. β 3 adrenergic receptor activation relaxes human corpus cavernosum and penile artery through a hydrogen sulfide/cGMP-dependent mechanism. Pharmacol Res  2017; 124: 100-4.
 [http://dx.doi.org/10.1016/j.phrs.2017.07.025] [PMID: 28760490]

[339]
Dayar E, Kara E, Yetik-Anacak G, et al. Do penile haemodynamics change in the presence of hydrogen sulphide (H 2 S) donor in metabolic syndrome-induced erectile dysfunction? Andrologia  2018; 50(3): e12885.
 [http://dx.doi.org/10.1111/and.12885] [PMID: 28901567]

[340]
Srilatha B, Muthulakshmi P, Adaikan PG, Moore PK. Endogenous hydrogen sulfide insufficiency as a predictor of sexual dysfunction in aging rats. Aging Male  2012; 15(3): 153-8.
 [http://dx.doi.org/10.3109/13685538.2012.668722] [PMID: 22455401]

[341]
Yilmaz-Oral D, Kaya-Sezginer E, Oztekin CV, Bayatli N, Lokman U, Gur S. Evaluation of combined therapeutic effects of hydrogen sulfide donor sodium hydrogen sulfide and phosphodiesterase type‐5 inhibitor tadalafil on erectile dysfunction in a partially bladder outlet obstructed rat model. Neurourol Urodyn  2020; 39(4): 1087-97.
 [http://dx.doi.org/10.1002/nau.24333] [PMID: 32150290]

[342]
Yilmaz E, Kaya-Sezginer E, Yilmaz-Oral D, Cengiz T, Bayatli N, Gur S. Effects of hydrogen sulphide donor, sodium hydrosulphide treatment on the erectile dysfunction in L‐NAME‐induced hypertensive rats. Andrologia  2019; 51(5): e13240.
 [http://dx.doi.org/10.1111/and.13240] [PMID: 30706510]

[343]
Zhang Y, Yang J, Wang T, et al. Decreased endogenous hydrogen sulfide generation in penile tissues of diabetic rats with erectile dysfunction. J Sex Med  2016; 13(3): 350-60.
 [http://dx.doi.org/10.1016/j.jsxm.2016.01.002] [PMID: 26853047]

[344]
Srilatha B, Adaikan PG, Moore PK. Possible role for the novel gasotransmitter hydrogen sulphide in erectile dysfunction—a pilot study. Eur J Pharmacol  2006; 535(1-3): 280-2.
 [http://dx.doi.org/10.1016/j.ejphar.2006.02.001] [PMID: 16527268]

[345]
Jupiter RC, Yoo D, Pankey EA, et al. Analysis of erectile responses to H 2 S donors in the anesthetized rat. Am J Physiol Heart Circ Physiol  2015; 309(5): H835-43.
 [http://dx.doi.org/10.1152/ajpheart.00293.2015] [PMID: 26116713]

[346]
La Fuente JM, Sevilleja-Ortiz A, García-Rojo E, et al. Erectile dysfunction is associated with defective L-cysteine/hydrogen sulfide pathway in human corpus cavernosum and penile arteries. Eur J Pharmacol  2020; 884: 173370.
 [http://dx.doi.org/10.1016/j.ejphar.2020.173370] [PMID: 32712093]

[347]
Olivencia MA, Esposito E, Brancaleone V, et al. Hydrogen sulfide regulates the redox state of soluble guanylate cyclase in CSE-/- mice corpus cavernosum microcirculation. Pharmacol Res  2023; 194: 106834.
 [http://dx.doi.org/10.1016/j.phrs.2023.106834] [PMID: 37343646]

[348]
Patel DP, Hotaling JM. Erectile dysfunction: Could it be genetic? J Sex Med  2020; 17(7): 1239-41.
 [http://dx.doi.org/10.1016/j.jsxm.2020.03.016] [PMID: 32387108]

[349]
Jorgenson E, Matharu N, Palmer MR, et al. Genetic variation in the SIM1 locus is associated with erectile dysfunction. Proc Natl Acad Sci USA  2018; 115(43): 11018-23.
 [http://dx.doi.org/10.1073/pnas.1809872115] [PMID: 30297428]

[350]
Atala A. Re: Genetic variation in the SIM1 locus is associated with erectile dysfunction. J Urol  2019; 201(6): 1056.
 [http://dx.doi.org/10.1097/JU.0000000000000215] [PMID: 30864912]

[351]
Bovijn J, Jackson L, Censin J, et al. GWAS Identifies Risk Locus for Erectile Dysfunction and Implicates Hypothalamic Neurobiology and Diabetes in Etiology. Am J Hum Genet  2019; 104(1): 157-63.
 [http://dx.doi.org/10.1016/j.ajhg.2018.11.004] [PMID: 30583798]

[352]
Patel CK, Bennett N. Advances in the treatment of erectile dysfunction: What’s new and upcoming? F1000 Res  2016; 5: 369.
 [http://dx.doi.org/10.12688/f1000research.7885.1] [PMID: 27516878]

[353]
Allen MS, Walter EE. Erectile Dysfunction: An umbrella review of meta-analyses of risk-factors, treatment, and prevalence outcomes. J Sex Med  2019; 16(4): 531-41.
 [http://dx.doi.org/10.1016/j.jsxm.2019.01.314] [PMID: 30833150]

[354]
Çayan S. Editorial commentary on “Erectile Dysfunction: An umbrella review of meta-analyses of risk factors, treatment, and prevalence outcomes”. J Sex Med  2019; 16(7): 1118.
 [http://dx.doi.org/10.1016/j.jsxm.2019.04.006] [PMID: 31103480]

[355]
Li JZ, Maguire TA, Zou KH, Lee LJ, Donde SS, Taylor DG. Prevalence, comorbidities, and risk factors of erectile dysfunction: Results from a prospective real-world study in the united kingdom. Int J Clin Pract  2022; 2022: 1-10.
 [http://dx.doi.org/10.1155/2022/5229702] [PMID: 35693549]

[356]
Kaya E, Sikka SC, Gur S. A comprehensive review of metabolic syndrome affecting erectile dysfunction. J Sex Med  2015; 12(4): 856-75.
 [http://dx.doi.org/10.1111/jsm.12828] [PMID: 25675988]

[357]
Lou IX, Chen J, Ali K, Chen Q. Relationship between hypertension, antihypertensive drugs and sexual dysfunction in men and women: A literature review. Vasc Health Risk Manag  2023; 19: 691-705.
 [http://dx.doi.org/10.2147/VHRM.S439334] [PMID: 37941540]

[358]
Terentes-Printzios D, Ioakeimidis N, Rokkas K, Vlachopoulos C. Interactions between erectile dysfunction, cardiovascular disease and cardiovascular drugs. Nat Rev Cardiol  2022; 19(1): 59-74.
 [http://dx.doi.org/10.1038/s41569-021-00593-6] [PMID: 34331033]

[359]
Fandel TM, Bella AJ, Lin G, et al. Intracavernous growth differentiation factor-5 therapy enhances the recovery of erectile function in a rat model of cavernous nerve injury. J Sex Med  2008; 5(8): 1866-75.
 [http://dx.doi.org/10.1111/j.1743-6109.2008.00881.x] [PMID: 18564148]
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DOI https://dx.doi.org/10.2174/0115743624302323240522101746	Print ISSN 1574-3624
Publisher Name Bentham Science Publisher	Online ISSN 2212-389X
Current Signal Transduction Therapy

Elucidating the Signaling Pathways Involved in Erectile Dysfunction

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