A sex-specific role for androgens in angiogenesis in vitro and in vivo

Background: The relationship between androgens and cardiovascular disease (CVD) remains poorly understood. While low testosterone levels in men are associated with increased mortality from CVD, the role of androgens in angiogenesis, a process critical in cardiovascular repair/regeneration, is unknown. Methods: We assessed the effect of the nonaromatisable androgen dihydrotestosterone (DHT) on key angiogenic events in male and female-donor endothelial cells (ECs). In vivo angiogenesis was assessed using 2 models: Matrigel plug; and hindlimb ischemia (HI) assays in castrate/ovariectomised and sham-operated male and female C57Bl6/J mice±DHT. Results: DHT induced a dose-dependent increase in migration, proliferation and tubulogenesis in male (P 0.05).Androgen Receptor (AR) antagonism and siRNA-knockdown abrogated DHT effects in male ECs. Gonadectomy markedly decreased Matrigel plug vascularisation in both sexes (P< 0.0001). However, this was reversed byDHT treatment in males (P < 0.02) but NOT females (Fig. 1). In males, blood-flow recovery fromHIwas impairedwith castration (P< 0.05), a finding also reversed by DHT (P< 0.01). DHT also increased mobilisation of erythroidand endothelial progenitor cells (P< 0.01). Conclusion:Androgensstimulatekeyangiogenicevents in males but NOT females in vitro and in vivo via AR. Androgens also stimulate progenitor cell mobilisation in males. These findings suggest that androgens may modulate vascular regeneration with implications for the role of androgen replacement in men.