Androgens Ameliorate Impaired Ischemia-Induced Neovascularization due to Aging in Male Mice.

There is abundant evidence that low circulating testosterone levels in older men is associated with adverse cardiovascular outcomes, however, the direction of causality is unclear. Although there is a burgeoning interest in the potential of androgen therapy in older men, the effect of androgens on cardiovascular regeneration in aging males remains poorly defined. We investigated the role of androgens in age-related impairment in ischemia-induced neovascularization. Castrated young (2-month) and old (24-month) male mice were subjected to unilateral hindlimb ischemia and treated with subdermal dihydrotestosterone (DHT) or placebo silastic implants. Blood flow recovery was enhanced by DHT treatment in young and old mice compared with age-matched placebo controls. DHT augmented angiogenesis in young mice and ameliorated age-related impairment in neovascularization in old mice. Administration of DHT was associated with increased hypoxia inducible factor-1α (HIF-1α) and stromal derived factor-1 expression in young mice, but not in old mice. In vitro, DHT induced HIF-1α transcriptional activation was attenuated in fibroblasts from old mice. Co-immunoprecipitation showed that interaction between androgen receptor (AR) and importins, key proteins that facilitate nuclear translocation of AR, was impaired with age. In contrast, DHT treatment stimulated the production and mobilization of Sca1+/CXCR4+ circulating progenitor cells in both young and old mice. DHT stimulated the migration and proangiogenic paracrine effect of ex vivo cultured bone marrow-derived angiogenic cells from young and old mice. In conclusion, androgens ameliorate age-related impairment in ischemia-induced neovascularization. While age-dependent dysfunction in androgen signaling attenuates some androgen effects on angiogenesis, pro-vasculogenic effects of androgens are partially preserved with age.