Permissive Role of GPER for Arterial Hypertension.

To the Editor: In women, arterial hypertension remains the main risk factor for coronary artery disease, heart failure, chronic kidney disease, and dementia. Hypertension prevalence increases after menopause and is associated with salt sensitivity. The Dahl rat model provides an excellent model to study the effects of ovarian hormones in the context of salt-sensitive hypertension. Similar to humans, ovary-intact female Dahl S rats have lower blood pressure than males, surgical menopause aggravates hypertension development, and hormone therapy alleviates it. Following its cloning in 1992, the orphan receptor GPR30 (G protein-coupled receptor 30) was subsequently identified as the first G protein–coupled receptor mediating steroid signaling. Its involvement in some of the rapid effects mediated by estrogen led to its designation as GPER (G protein–coupled estrogen receptor). However, GPER also mediates sustained chronic effects either requiring or independent of estrogen. Although GPER has been proposed as a GPCR (G protein-coupled receptor) for aldosterone, no binding of aldosterone to GPER has been documented despite effects mediated by cross talk between GPER and nuclear steroid receptors, including MR (mineralocorticoid receptor). Thus, there is no evidence to support the recent notion by Waghulde et al that “Gper1 is now recognized as a receptor for 2 ligands, estrogen and aldosterone”. Like most GPCRs, GPER also exerts ligand-independent, constitutive effects. NADPH (nicotinamide adenine dinucleotide phosphate) oxidase isoform Nox1 function is dependent on its constitutive induction by GPER (Figure) and either genetic deletion of GPER or its pharmacological inhibition protects from hypertension in male mice. Waghulde et al now confirmed these previous findings are demonstrating that deletion of Gper using CRISPR/Cas9 also reduces blood pressure in male and to an even greater extent in female Dahl S rats. Despite using only moderate amounts of dietary sodium (2% as opposed to 4% or even 8%) mean arterial blood pressure was 200 mm Hg in females and 180 mm Hg in males (230 and 200 mm Hg systolic, respectively). Not only were these blood pressure values much higher than those previously reported, but importantly pressure was higher in females. This is at variance with previous studies in ovary-intact female Dahl S rats displaying lower blood pressures than males. However, blood pressure-reducing effect of removing Gper from the genome was about double compared with males (≈40 versus 20 mm Hg), an effect was seen for mean, systolic, and diastolic blood pressure. This suggests that in females this pressure-lowering effect was partly due to endogenous estrogens via ERα, ERβ, or GPER and partly due to lack of GPER-dependent constitutive induction of Nox1. Whether microbiota contributed to the pressure-lowering effect remains uncertain as no differences were found in males. In fact, the authors noted that food intake alone might have altered the microbiome independent of genetic differences. Waghulde et al have generated the first GPER-deficient rat model. If CRISPR-CAS9 gene ablation of GPER would be available on a genetic background not prone to hypertension, this would also allow its study in obesity, chronic kidney disease, heart failure, stroke, and dementia. Like hypertension, these diseases are still on the rise globally and contribute to a large part of the economic and social burden of disease — in men and women alike.