Current Insights into the Role of HIF-1 in Cutaneous Wound Healing

E.      Andrikopoulou; X.      Zhang; R.      Sebastian; G.      Marti; L.      Liu; S.      M. Milner; J.      W. Harmon

doi:10.2174/156652411795243414

Abstract

Hypoxia Inducible Factor-1 (HIF-1) is considered the major coordinator of the cellular adaptive response to hypoxia. Over recent years, its activity in the context of wound healing has been the object of increasing investigation. On the molecular level, HIF-1 transcriptional target products have been shown to regulate the process of endothelial cell survival, migration and proliferation (VEGF, ANGPT-1, ANGPT-2, ANGPT-4, FGF-2, PlGF, PDGF-B, RGC-32), vascular smooth muscle cell migration and proliferation (FGF-2, EGF, PDGF, thrombospondin) and mobilization of Circulating Angiogenic Cells to the periphery (SFD- 1/CXCR4). Studies on the effect of HIF-1 on the expression and activity of extracellular cell matrix modifying enzymes, such as MMPs and prolidase, have been conducted in the context of tumor angiogenesis and metastasis, and have resulted in controversial findings. A growing body of evidence suggests that HIF-1 also affects reepithelialization of the wound bed, through increasing keratinocyte migration, but decreasing their proliferation. Diminished HIF-1 levels and activity have been documented in conditions of impaired wound healing, such as wound healing in aged and in diabetic mice. The increasing number of studies on the role of HIF-1 in wound healing, apart from answering certain questions, has also raised an equal number, if not more. Clarifying the topics that still remain unclear could introduce a new era of HIF-1 targeted management of a wide range of problematic wounds.

Keywords: Aging, angiogenesis, dermal wound healing, diabetes, hypoxia, Hypoxia Inducible Factor-1, hypovolemic shock, vasoconstricting drugs, homeostasis, neovascularization, dimerization, Hypoxia Responsive Elements, digoxin, Rapamycin, Geldanamycin