The role of androgens on hypoxia‐inducible factor (HIF)‐1α‐induced angiogenesis and on the survival of ischemically challenged skin flaps in a rat model

Abstract

Effects of androgens on angiogenesis are controversial. Hypoxia-inducible factor (HIF)-1α promotes expression of vascular endothelial growth factor (VEGF) that stimulates angiogenesis. This study investigates whether androgens stabilize HIF-1α in endothelial cells, and androgen depletion decreases VEGF concentrations and skin flap survival. Male human umbilical vein endothelial cells (HUVECs) were exposed to dihydrotestosterone (DHT) and HIF-1α expression was measured. In male Wistar rats, standardized proximally based random pattern dorsal skin flaps (3 × 9 cm) were raised 4 weeks after orchiectomy and sham operation, respectively (n = 10, each). Flap VEGF concentrations (immunohistochemistry), perfusion (Laser Doppler), and viability (digital planimetry) were measured. DHT induced HIF-1α expression in HUVECs. Androgen depletion induced decreased VEGF expression (P = 0.003), flap perfusion (P < 0.05), and survival (44.4% ± 5.2%) compared to controls (35.5% ± 4.5%; P = 0.003). In vitro, androgens may stimulate HIF-1α under normoxic conditions. In rats, androgen depletion decrease VEGF expression and flap survival.