Sex Differences in the Vasodilation Mediated by G Protein-Coupled Estrogen Receptor (GPER) in Hypertensive Rats

Abstract

BackgroundThe protective effect of estrogen on the vasculature cannot be explained only by its action through the receptors ERα and ERβ. G protein-coupled estrogen receptors (GPER)—which are widely distributed throughout the cardiovascular system—may also be involved in this response. However, little is known about GPER actions in hypertension. Therefore, in this study we evaluated the vascular response mediated by GPER using a specific agonist, G-1, in spontaneously hypertensive rats (SHR). We hypothesized that G-1 would induce a relaxing response in resistance mesenteric arteries from SHR of both sexes.MethodsG-1 concentration-response curves (1 nM-10 μM) were performed in mesenteric arteries from SHR of both sexes (10–12-weeks-old, weighing 180–250 g). The effects of G-1 were evaluated before and after endothelial removal and incubation for 30 min with the inhibitors L-NAME (300 μM) and indomethacin (10 μM) alone or combined with clotrimazole (0.75 μM) or catalase (1,000 units/mL). GPER immunolocalization was also investigated, and vascular hydrogen peroxide (H2O2) and ROS were evaluated using dichlorofluorescein (DCF) and dihydroethidium (DHE) staining, respectively.ResultsGPER activation promoted a similar relaxing response in resistance mesenteric arteries of female and male hypertensive rats, but with the participation of different endothelial mediators. Males appear to be more dependent on the NO pathway, followed by the H2O2 pathway, and females on the endothelium and H2O2 pathway.ConclusionThese findings show that the GPER agonist G-1 can induce a relaxing response in mesenteric arteries from hypertensive rats of both sexes in a similar way, albeit with differential participation of endothelial mediators. These results contribute to the understanding of GPER activation on resistance mesenteric arteries in essential hypertension.

Role of estrogen receptors in health and disease

“…GPER1 is widely distributed in the cardiovascular system and exerts protective effects on the vasculature ( 112 ). GPER1 decreases blood pressure, promotes vasodilation, and reduces the proliferation and migration of VSMCs ( 223 ).…”

Pathophysiology and Outcomes of Endothelium Function in Coronary Microvascular Diseases: A Systematic Review of Randomized Controlled Trials and Multicenter Study

“…Animal studies addressing EDH-mediated relaxations revealed a well-defined production of cyclooxygenases and NO synthase inhibitors that are coupled with hyperpolarization of VSMCs located in the proximity of these molecular reactions. Some experimental studies have established the heterogeneous nature of EDH factors by reporting the specific characteristics relating to the different species and vascular beds of concern [ 53 , 54 , 55 ]. Greater production of epoxyeicosatrienoic acids, which constitute the fundamental metabolites of the arachidonic P450 epoxygenase sequential reactions were noted [ 56 , 57 , 58 , 59 , 60 ].…”

Emerging Roles for G Protein-Coupled Estrogen Receptor 1 in Cardio-Renal Health: Implications for Aging

“…Evidence suggests that GPER1 stimulates NO production and promotes relaxation in multiple vascular beds [162][163][164][165][166]. GPER1 activation by G-1 increases NO in endothelial cells leading to vascular relaxation [162,164,165].…”