Androgen stimulates endothelial cell proliferation via an androgen receptor/VEGF/cyclin A-mediated mechanism

Abstract

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], but not 17β-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 D1, and 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, coadministration of SU5416 to 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. These results indicate that androgens acting on AR stimulate cell proliferation through upregulation of VEGF-A, cyclin A, and cyclin D1 in HAECs, which may be beneficial to cardiovascular functions since endothelial cell proliferation could assist the repair of endothelial injury/damage in cardiovascular system.

Roles of the Androgen – Androgen Receptor System in Vascular Angiogenesis

“…Androgens increase the expression of eNOS and enhance NO production through genomic and nongenomic effects of the AR in human umbilical vein endothelial cells (HUVECs), effects that were significantly reduced by AR blockade 60,61) . We also found that VEGF-stimulated Akt and that eNOS phosphorinjury and prevention of EC dysfunction 63) . In contrast, androgens have been shown to reduce proinflammatory cytokine production and adhesion molecular expression in several atherorelevant cells including monocytes, macrophages, ECs, VSMCs, and foam cells.…”

Hormonal effects on blood vessels

“…Cai et al 98 demonstrated that testosterone induced time-and dose-dependent proliferation of human aortic ECs via an AR-dependent pathway. In young hypogonadal men, low testosterone levels were associated with a small number of endothelial progenitor cells, 99 and testosterone replacement was able to increase the number of progenitor cells.…”

Effects of androgens on cardiovascular remodeling

“…As proof that the androgen-AR system is involved in angiogenesis, Sieveking et al (2010a) demonstrated both in vitro and in vivo that androgens elicit an AR-mediated angiogenic effect in males but not in females. They concluded that androgens promote angiogenesis via vascular endothelial growth factor (VEGF)-related mechanisms (Cai et al 2011) and also by stimulation of erythropoietin production (Sieveking et al 2010a,b). Further studies are necessary to clarify the significance of androgens in angiogenesis.…”