Androgens promote vascular endothelial cell proliferation through activation of a ZIP9-dependent inhibitory G protein/PI3K-Akt/Erk/cyclin D1 pathway

While androgens have been reported to mediate cardiovascular endothelial cell proliferation, the potential involvement of membrane androgen receptors (mAR) has not been examined. Here we show ZIP9, a recently characterized mAR, mediates androgen-induced early proliferative events in human umbilical vein endothelial cells (HUVECs). Androgen treatment significantly increased cyclin D1 nuclear localization and proliferation, which were blocked by transfection with siRNA targeting ZIP9 but not the nuclear AR. Testosterone rapidly activated inhibitory G protein signaling, Erk, and Akt, and inhibition of these signaling members abrogated the ZIP9-mediated cyclin D1 and proliferative responses. Erk and Akt modulated cyclin D1 nuclear localization by upregulation of cyclin D1 mRNA and inhibition of GSK-3β activity, respectively. This is the first study to demonstrate a role for ZIP9 in HUVEC proliferation and indicates ZIP9 is a physiologically-relevant androgen receptor in the cardiovascular system that merits further study as a potential therapeutic target for treating cardiovascular disease.