Androgen Stimulates Endothelial Cell Proliferation Via An Androgen Receptor-VEGF/Cyclin A Mechanism

Growing evidences support that androgen displays beneficial effects on cardiovascular functions although the mechanism of androgen actions remains to be elucidated. Modulation of endothelial cell growth and function is a potential mechanism of androgen actions. We demonstrated in the present study that androgens (dihydrotestosterone, DHT) and testosterone, T), but not17p-estradiol, produced a time and dose-dependent induction of cell proliferation in primary human aortic endothelial cells (HAECs) as evident by increases in viable cell number and DNA biosynthesis. Real-time qRT-PCR analysis showed that DHT induced androgen receptor (AR), cyclin A, cyclin D1and vascular endothelial growth factor (VEGF) gene expression in a dose and time-dependent manner. The addition of casodex, a specific AR antagonist, or transfection of a specific AR siRNA blocked DHT-induced cell proliferation and target gene expression, indicating that the DHT effects are mediated via AR. Moreover, co-administration of SU5416to block VEGF receptors, or transfection of a specific VEGF-A siRNA to knockdown VEGF expression, produced a dose-dependent blockade of DHT induction of cell proliferation and cyclin A gene expression. Interestingly, roscovitine, a selective cyclin-dependent kinase inhibitor, also blocked the DHT stimulation of cell proliferation with a selective inhibition of DHT-induced VEGF-A expression. In addition, dutasteride, a5α-reductase inhibitor, failed to inhibit T-induced HAEC growth. These results indicate that androgens acting on AR stimulate cell proliferation through upregulation of VEGF-A, cyclin A and cyclinD1gene expression in HAECs, which may be beneficial to cardiovascular functions as endothelial cell proliferation could assist the repair of endothelial injury/damage in cardiovascular system.