Abstract 5684: A Sex-Specific Role for Androgens in Angiogenesis
The role of androgens in cardiovascular disease remains controversial. Although men tend to develop CVD earlier than women, consistent with increased atherosclerosis, repair/adaptation mechanisms may be enhanced in males. For example, male gender is associated with increased collateralization in patients with severe coronary artery lesions. As angiogenesis, is critical to cardiovascular repair/regeneration, we hypothesized that androgens may modulate this process. We studied the effects of androgens on angiogenesis using human endothelial cells (ECs) and two distinct in vivo models. Dihydrotestosterone (DHT), a potent natural androgen specific for the androgen receptor (AR) augmented key angiogenic events in vitro, including EC migration, proliferation and tubulogenesis. Strikingly, this occurred in male but not female ECs. AR antagonism and siRNA-mediated knockdown abrogated all DHT effects in male ECs, while AR overexpression conferred androgen sensitivity in female ECs. In vivo, castration dramatically reduced vascularization of matrigel plugs in male and female mice. This reduction was fully reversed with DHT treatment in male but not female mice (Fig. 1⇓). Additionally, male castration impaired neovascularization and blood flow recovery in hindlimb ischemia, a finding that was rescued with DHT treatment. These findings were also mirrored in hypoxia inducible factor-1α and stromal cell-derived factor-1α expression, and the mobilzation of various angiogenic/progenitor cells. Our findings suggest endogenous androgens play an important role in angiogenesis in males but not females, with implications for the role of androgen replacement in men.