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Current Neurovascular Research

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ISSN (Print): 1567-2026
ISSN (Online): 1875-5739

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Research Article

Ang-1 Inhibited Endoplasmic Reticulum Stress and Apoptosis of VECs in Rats with aSAH-induced CVS Through the Regulated PI3K/Akt Pathway

Author(s): Pingbo Wei, Yangyun Han, Hao Chen, Le Luo, Gang Liu, Bing Lin, Hao Gong and Chao You*

Volume 20, Issue 1, 2023

Published on: 23 September, 2022

Page: [140 - 148] Pages: 9

DOI: 10.2174/1567202619666220412082145

Price: $65

Abstract

Aims: To explore angiopoietin-1 (Ang-1) involved in cerebral vasospasm (CVS) after aneurysmal subarachnoid hemorrhage (aSAH) through its effect on endoplasmic reticulum stress (ERS) and apoptosis of vascular endothelial cells (VECs).

Background: CVS accounts for high morbidity and mortality of aSAH. Abnormal cellular physiological processes of VECs play a critical role in aSAH-induced CVS. In addition, Ang-1 is involved in regulating vascular structure and function.

Objective: To study the role of Ang-1 played in CVS and the underlying mechanism.

Methods: Blood samples of 130 aSAH patients were collected from 2016 to 2020 at West China Hospital of Sichuan University. A two-hemorrhage rodent model was employed to structure an aSAH-induced CVS rat model. Moreover, oxyHb was used to treat VECs to construct a CVS cell model in vitro. ELISA was used to measure the level of Ang-1 and HE staining to assess the rat's basilar arteries. Subsequently, CCK-8 was used to detect cell viability ability, and flow cytometry was used to test the cell apoptosis rate. Western blotting was used to determine the expression level of ERS marker and apoptosis-related proteins.

Results: There was an abnormally low expression of Ang-1 in CVS patients and CVS rats; besides, oxyHb treatment decreased Ang-1 in VECs in a concentration-dependent manner. Ang-1 treatment led to the thinner basilar artery wall and lumen circumference in CVS rats; moreover, in oxyHbtreated VECs, Ang-1 treatment inhibited ERS and apoptosis. In addition, the expression of p-PI3K and p-Akt in the CVS group decreased, while the expression of p53 in the CVS group increased. The expression of p-PI3K and p-Akt in 8 CVS rats negatively correlates with the expression of Ang- 1, but the correlation between p53 and Ang-1 was positive. Furthermore, the results suggested that Ang-1 suppressed ERS and apoptosis of VECs through the regulated PI3K/Akt/p53 pathway.

Conclusion: Elevated Ang-1 inhibited p53-mediated ERS and apoptosis of VECs through the activated PI3K/Akt pathway; Ang-1 might be an attractive treatment strategy for CVS.

Keywords: Aneurysmal subarachnoid hemorrhage, cerebral vasospasm, angiopoietin-1, vascular endothelial cells, PI3K/Akt pathway, endoplasmic reticulum stress.

« Previous Next »
[1]
Olsen MH, Lilja-Cyron A, Bache S, Eskesen V, Møller K. Aneurysmal subarachnoid haemorrhage. Ugeskr Laeger 2019; 181(31): V01190019.
[PMID: 31368433]
[2]
Daou BJ, Koduri S, Thompson BG, Chaudhary N, Pandey AS. Clinical and experimental aspects of aneurysmal subarachnoid hemorrhage. CNS Neurosci Ther 2019; 25(10): 1096-112.
[http://dx.doi.org/10.1111/cns.13222] [PMID: 31583833]
[3]
Etminan N, Macdonald RL. Management of aneurysmal subarachnoid hemorrhage. Handb Clin Neurol 2017; 140: 195-228.
[http://dx.doi.org/10.1016/B978-0-444-63600-3.00012-X] [PMID: 28187800]
[4]
Rabinstein AA, Lanzino G. Aneurysmal Subarachnoid Hemorrhage: Unanswered Questions. Neurosurg Clin N Am 2018; 29(2): 255-62.
[http://dx.doi.org/10.1016/j.nec.2018.01.001] [PMID: 29502715]
[5]
Li K, Barras CD, Chandra RV, et al. A review of the management of cerebral vasospasm after aneurysmal subarachnoid hemorrhage. World Neurosurg 2019; 126: 513-27.
[http://dx.doi.org/10.1016/j.wneu.2019.03.083] [PMID: 30898740]
[6]
Chugh C, Agarwal H. Cerebral vasospasm and delayed cerebral ischemia: Review of literature and the management approach. Neurol India 2019; 67(1): 185-200.
[PMID: 30860121]
[7]
Baggott CD, Aagaard-Kienitz B. Cerebral vasospasm. Neurosurg Clin N Am 2014; 25(3): 497-528.
[http://dx.doi.org/10.1016/j.nec.2014.04.008] [PMID: 24994087]
[8]
Chen S, Wu H, Tang J, Zhang J, Zhang JH. Neurovascular events after subarachnoid hemorrhage: Focusing on subcellular organelles. Acta neurochirurgica Supplement 2015; 120: 39-46.
[http://dx.doi.org/10.1007/978-3-319-04981-6_7]
[9]
Schwarz DS, Blower MD. The endoplasmic reticulum: Structure, function and response to cellular signaling. Cell Mol Life Sci 2016; 73(1): 79-94.
[http://dx.doi.org/10.1007/s00018-015-2052-6] [PMID: 26433683]
[10]
Wang M, Kaufman RJ. Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature 2016; 529(7586): 326-35.
[http://dx.doi.org/10.1038/nature17041] [PMID: 26791723]
[11]
Almanza A, Carlesso A, Chintha C, et al. Endoplasmic reticulum stress signalling - from basic mechanisms to clinical applications. FEBS J 2019; 286(2): 241-78.
[http://dx.doi.org/10.1111/febs.14608 ] [PMID: 30027602]
[12]
Zubkov AY, Ogihara K, Bernanke DH, Parent AD, Zhang J. Apoptosis of endothelial cells in vessels affected by cerebral vasospasm. Surg Neurol 2000; 53(3): 260-6.
[http://dx.doi.org/10.1016/S0090-3019(99)00187-1] [PMID: 10773259]
[13]
Asano T. Oxyhemoglobin as the principal cause of cerebral vasospasm: A holistic view of its actions. Crit Rev Neurosurg 1999; 9(5): 303-18.
[http://dx.doi.org/10.1007/s003290050147] [PMID: 10525849]
[14]
Meguro T, Klett CP, Chen B, Parent AD, Zhang JH. Role of calcium channels in oxyhemoglobin-induced apoptosis in endothelial cells. J Neurosurg 2000; 93(4): 640-6.
[http://dx.doi.org/10.3171/jns.2000.93.4.0640] [PMID: 11014543]
[15]
Fagiani E, Christofori G. Angiopoietins in angiogenesis. Cancer Lett 2013; 328(1): 18-26.
[http://dx.doi.org/10.1016/j.canlet.2012.08.018] [PMID: 22922303]
[16]
Chittiboina P, Ganta V, Monceaux CP, Scott LK, Nanda A, Alexander JS. Angiopoietins as promising biomarkers and potential therapeutic targets in brain injury. Pathophysiology 2013; 20(1): 15-21.
[http://dx.doi.org/10.1016/j.pathophys.2012.02.004]
[17]
Findlay JM, Nisar J, Darsaut T. Cerebral vasospasm: A review. Can J Neurol Sci 2016; 43(1): 15-32.
[http://dx.doi.org/10.1017/cjn.2015.288]
[18]
Reynolds RA, Amin SN, Jonathan SV, et al. Hyperoxemia and cerebral vasospasm in aneurysmal subarachnoid hemorrhage. Neurocrit Care 2021; 35(1): 30-8.
[http://dx.doi.org/10.1007/s12028-020-01136-6] [PMID: 33150573]
[19]
Gu H, Fei ZH, Wang YQ, et al. Angiopoietin-1 and Angiopoietin-2 expression imbalance influence in early period after subarachnoid hemorrhage. Int Neurourol J 2016; 20(4): 288-95.
[http://dx.doi.org/10.5213/inj.1632692.346] [PMID: 28043115]
[20]
Wang Y, Tian Y, Wang D, et al. High Angiopoietin-1 levels predict a good functional outcome within 72 h of an aneurysmal subarachnoid hemorrhage: A prospective study from a single center. J Neurol Sci 2015; 356(1-2): 72-6.
[http://dx.doi.org/10.1016/j.jns.2015.05.038] [PMID: 26208799]
[21]
Fischer M, Broessner G, Dietmann A, et al. Angiopoietin-1 is associated with cerebral vasospasm and delayed cerebral ischemia in subarachnoid hemorrhage. BMC Neurol 2011; 11(1): 59.
[http://dx.doi.org/10.1186/1471-2377-11-59] [PMID: 21615958]
[22]
Shi C, Shen C, Liu G, et al. NEAT1 promotes the repair of abdominal aortic aneurysms of endothelial progenitor cells via regulating miR-204-5p/Ang-1. Am J Transl Res 2021; 13(4): 2111-26.
[PMID: 34017378]
[23]
Miao H, Qiu F, Zhu L, et al. Novel angiogenesis strategy to ameliorate pulmonary hypertension. J Thorac Cardiovasc Surg 2021; 161(6): e417-34.
[http://dx.doi.org/10.1016/j.jtcvs.2020.03.044] [PMID: 32359908]
[24]
Son Y, Cox JM, Stevenson JL, Cooper JA, Paton CM. Angiopoietin-1 protects 3T3-L1 preadipocytes from saturated fatty acid-induced cell death. Nutr Res 2020; 76: 20-8.
[http://dx.doi.org/10.1016/j.nutres.2020.02.007] [PMID: 32146252]
[25]
Hosoi T, Tamubo T, Horie N, Okuma Y, Nomura Y, Ozawa K. TEK/Tie2 is a novel gene involved in endoplasmic reticulum stress. J Pharmacol Sci 2010; 114(2): 230-3.
[http://dx.doi.org/10.1254/jphs.10082SC] [PMID: 20938104]
[26]
Engin H. Ustündağ Y, Ozel Tekin I, Gökmen A. Plasma concentrations of Ang-1, Ang-2 and Tie-2 in gastric cancer. Eur Cytokine Netw 2012; 23(1): 21-4.
[http://dx.doi.org/10.1684/ecn.2012.0301] [PMID: 22449617]
[27]
Zeng K, Ming J, Yang N, et al. Taurine prevents high glucose-induced angiopoietin-2/tie-2 system alterations and apoptosis in retinal microvascular pericytes. Mol Cell Biochem 2014; 396(1-2): 239-48.
[http://dx.doi.org/10.1007/s11010-014-2159-3] [PMID: 25060907]
[28]
Harel S, Sanchez V, Moamer A, et al. ETS1, ELK1, and ETV4 transcription factors regulate Angiopoietin-1 signaling and the angiogenic response in endothelial cells. Front Physiol 2021; 12: 683651.
[http://dx.doi.org/10.3389/fphys.2021.683651] [PMID: 34381375]
[29]
Echavarria R, Hussain SN. Regulation of angiopoietin-1/Tie-2 receptor signaling in endothelial cells by dual-specificity phosphatases 1, 4, and 5. J Am Heart Assoc 2013; 2(6): e000571.
[http://dx.doi.org/10.1161/JAHA.113.000571] [PMID: 24308939]
[30]
Zhao J, Yang S, Shu B, et al. Transient high glucose causes persistent vascular dysfunction and delayed wound healing by the DNMT1-mediated Ang-1/NF-κB pathway. J Invest Dermatol 2021; 141(6): 1573-84.
[http://dx.doi.org/10.1016/j.jid.2020.10.023] [PMID: 33259831]
[31]
Niu Q, Perruzzi C, Voskas D, Lawler J, Dumont DJ, Benjamin LE. Inhibition of Tie-2 signaling induces endothelial cell apoptosis, decreases Akt signaling, and induces endothelial cell expression of the endogenous anti-angiogenic molecule, thrombospondin-1. Cancer Biol Ther 2004; 3(4): 402-5.
[http://dx.doi.org/10.4161/cbt.3.4.735] [PMID: 14739779]
[32]
Chen Q, Ye ZN, Liu JP, et al. Elevated cerebrospinal fluid levels of thrombospondin-1 correlate with adverse clinical outcome in patients with aneurysmal subarachnoid hemorrhage. J Neurol Sci 2016; 369: 126-30.
[http://dx.doi.org/10.1016/j.jns.2016.08.017] [PMID: 27653877]
[33]
Luo X, Lin B, Gao Y, et al. Genipin attenuates mitochondrial-dependent apoptosis, endoplasmic reticulum stress, and inflammation via the PI3K/AKT pathway in acute lung injury. Int Immunopharmacol 2019; 76: 105842.
[http://dx.doi.org/10.1016/j.intimp.2019.105842] [PMID: 31466050]
[34]
Zhao G, Zhang X, Wang H, Chen Z. Beta carotene protects H9c2 cardiomyocytes from advanced glycation end product-induced endoplasmic reticulum stress, apoptosis, and autophagy via the PI3K/Akt/mTOR signaling pathway. Ann Transl Med 2020; 8(10): 647.
[http://dx.doi.org/10.21037/atm-20-3768] [PMID: 32566584]
[35]
Lin Q, Wang W, Yang L, Duan X. 4-Methoxybenzylalcohol protects brain microvascular endothelial cells against oxygen-glucose deprivation/reperfusion-induced injury via activation of the PI3K/AKT signaling pathway. Exp Ther Med 2021; 21(3): 252.
[http://dx.doi.org/10.3892/etm.2021.9684] [PMID: 33613705]
[36]
Sicari D, Fantuz M, Bellazzo A, et al. Mutant p53 improves cancer cells’ resistance to endoplasmic reticulum stress by sustaining activation of the UPR regulator ATF6. Oncogene 2019; 38(34): 6184-95.
[http://dx.doi.org/10.1038/s41388-019-0878-3] [PMID: 31312025]
[37]
López I, Tournillon AS, Prado Martins R, et al. p53-mediated suppression of BiP triggers BIK-induced apoptosis during prolonged endoplasmic reticulum stress. Cell Death Differ 2017; 24(10): 1717-29.
[http://dx.doi.org/10.1038/cdd.2017.96] [PMID: 28622297]
[38]
Tan X, Cai D, Chen N, et al. Methamphetamine mediates apoptosis of vascular smooth muscle cells via the chop-related endoplasmic reticulum stress pathway. Toxicol Lett 2021; 350: 98-110.
[http://dx.doi.org/10.1016/j.toxlet.2021.06.019] [PMID: 34214594]
[39]
Giorgi C, Bonora M, Sorrentino G, et al. p53 at the endoplasmic reticulum regulates apoptosis in a Ca2+-dependent manner. Proc Natl Acad Sci USA 2015; 112(6): 1779-84.
[http://dx.doi.org/10.1073/pnas.1410723112] [PMID: 25624484]
[40]
Zhou C, Yamaguchi M, Colohan AR, Zhang JH. Role of p53 and apoptosis in cerebral vasospasm after experimental subarachnoid hemorrhage. J Cereb Blood Flow Metab 2005; 25(5): 572-82.
[http://dx.doi.org/10.1038/sj.jcbfm.9600069] [PMID: 15729295]
[41]
Cahill J, Calvert JW, Solaroglu I, Zhang JH. Vasospasm and p53-induced apoptosis in an experimental model of subarachnoid hemorrhage. Stroke 2006; 37(7): 1868-74.
[http://dx.doi.org/10.1161/01.STR.0000226995.27230.96] [PMID: 16741174]
[42]
Yan JH, Yang XM, Chen CH, et al. Pifithrin-alpha reduces cerebral vasospasm by attenuating apoptosis of endothelial cells in a subarachnoid haemorrhage model of rat. Chin Med J (Engl) 2008; 121(5): 414-9.
[http://dx.doi.org/10.1097/00029330-200803010-00009] [PMID: 18364113]

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