title: Aging impairs VEGF-mediated, androgen-dependent regulation of angiogenesis.
abstract: There is a progressive impairment of vascular repair mechanisms with advancing age concomitant with a steady decline in circulating androgen levels in men. Emerging evidence indicates androgens regulate angiogenesis; however, little research has focused on the impact of age upon androgen-mediated regulation of angiogenic mechanisms. Human dermal fibroblasts from young (<30 years) and older (>65 years) men were incubated with DHT, with or without androgen receptor antagonist hydroxyflutamide, or phosphoinositide 3-kinase inhibitor. Fibroblast-conditioned medium was used to stimulate angiogenic functions in human umbilical vein endothelial cells. Nuclear fractionation and fluorescence microscopy were used to study androgen receptor (AR) distribution. Conditioned medium from fibroblasts of young men, but not old men, treated with DHT produced a 3-fold increase in human umbilical vein endothelial cell tubulogenesis and 2-fold increase in migration via increased vascular endothelial growth factor (VEGF) expression and secretion, predominantly of VEGF145. DHT-induced VEGF secretion from fibroblasts of young men was AR-dependent and increased AKT phosphorylation, which was abrogated by phosphoinositide 3-kinase inhibition. By contrast, fibroblasts from older men were unresponsive to DHT and lacked androgen-mediated enhancement in VEGF production. These findings were associated with reduced AR nuclear translocation in old fibroblasts. The failure of DHT-induced paracrine stimulation of angiogenesis in fibroblasts from older men is likely due to defective nuclear translocation of AR. This first demonstration of androgen resistance (or insensitivity) acquired by human fibroblasts with aging suggests that pharmacological testosterone therapy for old men may be less effective in enhancing angiogenesis and facilitating tissue regeneration mechanisms reliant on paracrine release of VEGF.
authors: The Heart Research Institute (L.L., Y.T.L., S.C.Y., P.J.L.S., M.K.C.N.), Newtown NSW Australia 2042; School of Medical Sciences (L.L., Y.T.L., L.A.L., S.C.Y., P.J.L.S., D.J.H., M.K.C.N.), The University of Sydney, New South Wales Australia 2006; ANZAC Research Institute (D.J.H.), University of Sydney, Concord Hospital New South Wales Australia 2139; and Royal Prince Alfred Hospital (M.K.C.N.), Camperdown New South Wales Australia 2050.
authors: Laura
authors: L
authors: Lecce
authors: Yuen Ting
authors: YT
authors: Lam
authors: Laura A
authors: LA
authors: Lindsay
authors: Sui Ching
authors: SC
authors: Yuen
authors: Philippa J L
authors: PJ
authors: Simpson
authors: David J
authors: DJ
authors: Handelsman
authors: Martin K C
authors: MK
authors: Ng
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging; D000728:Androgens / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D003593:Cytoplasm / Q000378:metabolism; D013196:Dihydrotestosterone / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008297:Male; D018919:Neovascularization, Physiologic; D034741:RNA, Small Interfering / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D012867:Skin / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D000728:Androgens; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D013196:Dihydrotestosterone; D008156:Luciferases