Abstract
Our previous work showed that the G protein-coupled estrogen receptor (GPER) is protective in the vasculature and kidneys during angiotensin (Ang) II-dependent hypertension by inhibiting oxidative stress. The goal of the current study was to assess the impact of GPER deletion on sex differences in Ang II-induced hypertension and oxidative stress. Male and female wildtype and GPER knockout mice were implanted with radiotelemetry probes for measurement of baseline blood pressure before infusion of Ang II (700 ng/kg/min) for 2 weeks. Mean arterial pressure was increased to the same extent in all groups, but female wildtype mice were protected from Ang II-induced increases in pulse pressure, aortic wall thickness, and Nox4 mRNA. In vitro studies using vascular smooth muscle cells found that pre-treatment with the GPER agonist G-1 inhibited Ang II-induced ROS and NADP/NADPH. Ang II increased while G-1 decreased Nox4 mRNA and protein. The effects of Ang II were blocked by losartan and Nox4 siRNA, while the effects of G-1 were inhibited by adenylyl cyclase inhibition and mimicked by phosphodiesterase inhibition. We conclude that during conditions of elevated Ang II, GPER via the cAMP pathway suppresses Nox4 transcription to limit ROS production and prevent arterial stiffening. Taken together with our previous work, this study provides insight into how acute estrogen signaling via GPER provides cardiovascular protection during Ang II hypertension and potentially other diseases characterized by increased oxidative stress.
Highlights
Premenopausal women are protected from cardiovascular disease compared with age-matched men, while aging narrows this sex difference [1]
The novel finding from the current study is that despite similar blood pressures, G protein-coupled estrogen receptor (GPER) deletion in female mice significantly increased pulse pressure and exacerbated the upregulation of aortic NADPH oxidases in response to angiotensin II (Ang II)
We demonstrated that Nox4 plays a major role in Ang II-induced Reactive oxygen species (ROS) production in cultured VSMC
Summary
Premenopausal women are protected from cardiovascular disease compared with age-matched men, while aging narrows this sex difference [1]. The G protein-coupled estrogen receptor (GPER), previously known as GPR30, mediates non-genomic signaling by estrogen and is expressed in vascular endothelial and smooth muscle cells [2,3,4]. Global GPER deletion does not impact reproductive function yet induces a variety of cardiometabolic deficits [13] including increased fat mass [14, 15], atherosclerosis [16], blood pressure, and glucose intolerance [17]. While GPER is expressed in the vasculature of both sexes [19, 20], the protective effects of GPER seem to be reversed in aging male mice, where global GPER deletion is protective against cardiac and vascular dysfunction [21, 22]. Many of the cardiovascular effects of GPER are associated with changes in reactive oxygen species, suggesting an antioxidant role for this estrogen receptor
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