Biomedical Sciences ETDs

Publication Date



Regulation of arterial tone relies heavily on molecular crosstalk between endothelial and smooth muscle cells. Although it has been demonstrated that estrogen (E2) exerts protective effects against cardiovascular disease (CVD), the exact mechanisms and balance of E2 signaling in endothelial and smooth muscle cells remain unresolved. Here we characterize the G protein-coupled estrogen receptor (GPER) in the vasculature by elucidating its pathway in endothelial nitric oxide (NO) production and vascular smooth muscle maintenance of reactive oxygen species (ROS) by NADPH oxidases (NOX). NO is thought of as a vasoprotective entity, while the overproduction of ROS by NOX can lead to vascular dysfunction. These two forces counteract each other to maintain arterial tone, and understanding their mediation by GPER will provide significant insights in sex differences in vascular function. In endothelial cells, we demonstrated that GPER activation induces phosphorylation of eNOS at ser1179, and contributes to ER-dependent NO production. Inhibition of GPER through pharmacologic antagonism (G36) or genomic deletion (GPER KO) reduced NO production and vasorelaxation to E2. We also found that NO production by selective estrogen receptor modifiers and downregulators (SERMs/SERDs), known to antagonize classic ERs and agonize GPER, was only partially abrogated by GPER inhibition, suggesting that there may be E2- independent targeting effects by these compounds. In the smooth muscle we were surprised to find that the arteries of GPER KO animals exhibited a reduced contraction response to Ang II. We characterized a novel pathway in which GPER mediates genomic expression of the NOX1 subunit in smooth muscle cells. Critically, we report that GPER inhibition or deletion reduces or blocks the hypertensive response to Ang II in mice. Taken together, these data describe a counterintuitive paradigm in which GPER signaling is important for E2-mediated NO production at the endothelium through acute eNOS activation, but conversely is involved in ROS generation at the smooth muscle though expression of NOX1. In lieu of the conflicting CVD reported for E2 replacement in post-menopausal women, we propose that the signaling pathway(s) of GPER may increase ROS production through smooth muscle NOX1 expression, which may override endothelial NO production, resulting in vascular dysfunction.


superoxide, G protein coupled estrogen receptor, nitric oxide, hypertension


National Institutes of Health Vascular Physiology training grant

Document Type




Degree Name

Biomedical Sciences

Level of Degree


Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Hathaway, Helen

Second Committee Member

Resta, Thomas

Third Committee Member

Nikki, Jernigan

Fourth Committee Member

Robert, Orlando