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Gene & Protein in Disease GPER1 in brain and heart diseases

monophosphate pathway. Mice lacking GPER1 vasodilation in both sexes of spontaneous hypertensive
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exhibited increased endothelium-dependent contractility rats through different intracellular signaling pathways
compared with normal mice, as G-1-induced GPER1 such as the H O and NO pathways. In male rats, the
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activation beneficially suppresses cyclooxygenase- relaxing response in the mesenteric arteries involves the
derived endothelium-derived contractile factors such NO pathway, whereas in female rats, the H O pathway is
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as endothelin1. Other reports of GPER1 activation predominant. In conclusion, these data suggest a central
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involved in the molecular pathways of vascular dilatation regulatory role of GPER1 in hypertension and indicate a
and relaxation have revealed the involvement of Rho- role of GPER1 agonists in the treatment of cardiovascular
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kinase-dependent and cAMP-dependent mechanisms. diseases in both biological sexes, placing a special focus on
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Activation of GPER1 through its highly selective agonist personalized approaches to treat these diseases in women
G-1 results in vasodilation of arteries and vasodilatation (Figure 2).
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is maximal in postmenopausal woman compared with age-
matched men. Genetic linkage studies have corroborated 3.2. Cardiovascular function
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the role of GPER1 in regulating blood pressure, as GWAS One of the most frequent causes of heart failure is the loss
have demonstrated that a genetic region associated with of contractile tissue after myocardial infarction, resulting
arterial hypertension is consistent with the location in either heart failure with reduced ejection fraction
of GPER1. Mechanistically, a single-nucleotide (HFrEF) or heart failure with preserved ejection fraction
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polymorphism (rs1154431) results in a substitution of (HFpEF). Remarkably, there is a marked sex-specific
leucine with proline at position 16 (GPER1 p.P16L), with difference between men and women, as the prevalence of
a relative common allele frequency of ~20%. This results HFpEF in women is higher, with 1% in women and 0%
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in a hypofunctional receptor leading to an increased blood in men in the age of 25 – 49 years and 8 – 10% in women
pressure in female rats but not in male rats, probably due aged >80 years compared to 4 – 6% in men of the same age.
to a lower activation level of ERK1/2 observed in a rat Men show an almost two-fold higher risk of HFrEF but not
vascular smooth muscle cell line. A study using patient- for HFpEF than women. In a mouse model of induced
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derived induced pluripotent stem cell models from three heart failure through pressure overload, estrogen therapy
female patients with hypertension and heterozygous could restore the ejection fraction (not further specified)
GPER1 p.P16L and CRISPR/Cas9 gene-edited isogenic of induced heart failure from 0.35 to a normal value of
normal controls indicated the specific involvement of 0.53 by stimulating angiogenesis, suppressing fibrosis,
GPER1 in the development of hypertension. This study and improving cardiac hemodynamics in both sexes,
showed that the L16 variant reduced the anti-inflammatory indicating a protective role of E2 through sarcoplasmic/
effects of GPER1 in induced pluripotent stem cell-derived endoplasmic reticulum calcium ATPase activation.
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endothelial cells (iECs), and normal GPER1 plays a role Furthermore, hypoxia or hypoxemia during myocardial
in the regulation of cell adhesion molecules, as shown infarction can trigger the upregulation of GPER1 mRNA
in a monocyte-to-iEC adhesion assay. Although the and GPER1 protein level in ERα- and ERβ-negative
polymorphism in these patients did not significantly affect human breast adenocarcinoma cells (SKBR3) and HL-1
endothelial NO synthase and NO production compared mouse cardiac muscle cells, 222,224 although there are yet
with isogenic normal P16 or hypertension-associated L16 no further data concerning GPER1 epigenetics in human
GPER1, these findings suggest that a modest elevation cardiomyocytes. GPER1 has been identified as a major
of inflammation can induce a mechanism contributing player of cardioprotection in female and male Sprague–
to elevated blood pressure and the risk of developing Dawley rats, based on the observation that activation
hypertension. Another study reported that acute of GPER1 with G-1 supported functional recovery after
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activation of GPER1 with the selective agonist G-1 resulted ischemia and reduced infarct size independently from
in vasodilatation in human endothelial cells through the biological sex. Nevertheless, sex-specific differences were
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liberation of NO. At present, there are no data on whether detected in cardiomyocyte-specific GPER1 KO mice with
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the GPER1 p.P16L single-nucleotide polymorphisms play pronounced impaired systolic and diastolic function in
a role in cardiovascular function in men. male compared with female KO mice. In addition, DNA
Aging and the consequent decreased estrogen level microarray analysis revealed sex-specific differences in the
are some of the primary factors that reduce GPER1- gene expression profiles of the transcriptional networks
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dependent vasodilatation. Studies have shown that E2 in a cardiomyocyte-specific GPER1 KO mouse model.
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administration elicits blood pressure-lowering effects in Interestingly, Wang et al. demonstrated that the gene set
different mammalian 218,219 and human models. Moreover, enrichment analysis of transcriptional networks revealed
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the activation of GPER1 through G-1 results in similar an enrichment of mitochondrial genes only in females
Volume 4 Issue 1 (2025) 13 doi: 10.36922/gpd.4632