A sex-specific role for androgens in angiogenesis.
Mounting evidence suggests that in men, serum levels of testosterone are negatively correlated to cardiovascular and all-cause mortality. We studied the role of androgens in angiogenesis, a process critical in cardiovascular repair/regeneration, in males and females. Androgen exposure augmented key angiogenic events in vitro. Strikingly, this occurred in male but not female endothelial cells (ECs). Androgen receptor (AR) antagonism or gene knockdown abrogated these effects in male ECs. Overexpression of AR in female ECs conferred androgen sensitivity with respect to angiogenesis. In vivo, castration dramatically reduced neovascularization of Matrigel plugs. Androgen treatment fully reversed this effect in male mice but had no effect in female mice. Furthermore, orchidectomy impaired blood-flow recovery from hindlimb ischemia, a finding rescued by androgen treatment. Our findings suggest that endogenous androgens modulate angiogenesis in a sex-dependent manner, with implications for the role of androgen replacement in men.
Sieveking
Daniel P
DP
Heart Research Institute, Sydney 2042, Australia. sievekingd@hri.org.au
Lim
Patrick
P
Chow
Renée W Y
RW
Dunn
Louise L
LL
Bao
Shisan
S
McGrath
Kristine C Y
KC
Heather
Alison K
AK
Handelsman
David J
DJ
Celermajer
David S
DS
Ng
Martin K C
MK
D059002:Androgen Receptor Antagonists; D000818:Animals; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D002369:Castration; D013196:Dihydrotestosterone / Q000378:metabolism* / Q000494:pharmacology; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D007511:Ischemia / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D011944:Receptors, Androgen / Q000096:biosynthesis; D020127:Recovery of Function; D012737:Sex Factors
D059002:Androgen Receptor Antagonists; D011944:Receptors, Androgen; D013196:Dihydrotestosterone