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.
BACKGROUND
Effects of androgens on angiogenesis are controversial. Hypoxia-inducible factor (HIF)-1α promotes expression of vascular endothelial growth factor (VEGF) that stimulates angiogenesis.


OBJECTIVE
This study investigates whether androgens stabilize HIF-1α in endothelial cells, and androgen depletion decreases VEGF concentrations and skin flap survival.


METHODS
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.


RESULTS
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).


CONCLUSIONS
In vitro, androgens may stimulate HIF-1α under normoxic conditions. In rats, androgen depletion decrease VEGF expression and flap survival.
Department of Plastic, Reconstructive and Hand Surgery, University Hospital, Inselspital, University of Berne, Switzerland. maziar_shafighi@yahoo.com
Maziar
M
Shafighi
Radu
R
Olariu
Claudio
C
Brun
Ali R
AR
Fathi
Siamak
S
Djafarzadeh
Stephan M
SM
Jakob
Robert E
RE
Hunger
Andrej
A
Banic
Mihai A
MA
Constantinescu
D000728:Androgens / Q000502:physiology*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D013196:Dihydrotestosterone; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D007511:Ischemia; D017078:Laser-Doppler Flowmetry; D008297:Male; D018919:Neovascularization, Physiologic / Q000502:physiology*; D009919:Orchiectomy; D051381:Rats; D017208:Rats, Wistar; D013524:Surgical Flaps / Q000098:blood supply* / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D014945:Wound Healing / Q000502:physiology
D000728:Androgens; D015415:Biomarkers; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D013196:Dihydrotestosterone