Overexpressed HIF-2α in Endothelial Cells Promotes Vascularization and Improves Random Pattern Skin Flap Survival

Abstract

Background:The local skin flap procedure is very useful for reconstruction. However, flap necrosis caused by circulatory failure can occur at its distal portion. Hypoxia-inducible factors (HIFs) in endothelial cells (ECs) help to maintain ECs and promote vascularization, and HIF-2α is abundantly expressed in ECs. However, the mechanisms of action of HIF-2α in ECs are not yet fully understood. The aim of this study was to evaluate the in vivo effects of overexpression of HIF-2α in ECs on skin flap survival.Methods:A random pattern skin flap (1.0 × 3.0 cm) was elevated on the dorsum of transgenic mice (Tg mice) with EC-specific HIF-2α conditional overexpression and wild-type littermate control mice (n = 6). Flap survival was evaluated on postoperative day 7. Tissue samples from the skin flaps were harvested and analyzed using Western blotting, quantitative reverse transcriptase-polymerase chain reaction, and immunohistochemistry.Results:The HIF-2α mRNA and protein levels were significantly increased in the Tg mice when compared with control mice. Tg mice had significantly increased skin flap survival areas (72.0% ± 2.7%) when compared with wild-type mice (45.7% ± 1.1%). Moreover, histological examination revealed an increase in the subcutaneous blood vessel counts in the Tg mice.Conclusions:Specific overexpression of HIF-2α in ECs promoted vascularization and enhanced skin flap survival in vivo in a mouse model.