Aging Impairs VEGF-Mediated, Androgen-Dependent Regulation of Angiogenesis

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 re...

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Bibliographic Details
Published in:Molecular endocrinology (Baltimore, Md.) Md.), 2014-09, Vol.28 (9), p.1487-1501
Main Authors: Lecce, Laura, Lam, Yuen Ting, Lindsay, Laura A, Yuen, Sui Ching, Simpson, Philippa J. L, Handelsman, David J, Ng, Martin K. C
Format: Article
Language:English
Subjects:
Adult
Age Factors
Aged
Aged, 80 and over
Aging
Androgens - metabolism
Cell Nucleus - metabolism
Cell Proliferation
Cytoplasm - metabolism
Dihydrotestosterone - pharmacology
Fibroblasts - metabolism
Gene Expression Regulation
Human Umbilical Vein Endothelial Cells
Humans
Luciferases - metabolism
Male
Neovascularization, Physiologic
Original Research
Receptors, Androgen - metabolism
RNA, Small Interfering - metabolism
Skin - metabolism
Vascular Endothelial Growth Factor A - metabolism
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Summary: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 (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.
ISSN:0888-8809
1944-9917
DOI:10.1210/me.2013-1405