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Gene & Protein in Disease GPER1 in brain and heart diseases

neurological diseases, MS exhibits an imbalance in sex 3. GPER1 and its role in cardiovascular
distribution, as its prevalence is higher in women than diseases
in men, with a ratio of approximately 3:1 reported in
Europe. A prominent initial study on the influence of 3.1. Hypertension
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pregnancies on MS revealed a strong reduction in relapse Hypertension is a polyfactorial disease that can manifest as
rates during pregnancies, emphasizing the vital role severe cardiovascular pathologies over time, such as heart
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of sex hormones in the pathophysiology of neurological failure and stroke. Clinically, it is defined as a sustained
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diseases. As already discussed in the neuroinflammation resting systolic blood pressure level of ≥130 mmHg or a
section (2.1), GPER1 activation may play a role in the diastolic blood pressure level of ≥80 mmHg. There
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regulation of neuroinflammation acting on microglia, is extensive evidence that estrogen confers protection
astrocytes, and cytokine release, suggesting its importance against cardiovascular diseases, particularly coronary
in MS. This was confirmed by Blasko et al., who reported heart disease, heart failure, and arterial hypertension, in
an inhibition of LPS-induced cytokine production in premenopausal women. Interestingly, the blood pressure
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human macrophages by the activation of GPER1 through increases in postmenopausal women 5 – 10 years after
its agonist G-1. Moreover, in vivo data have corroborated the cessation of estrus cycling, such that the prevalence of
these results, wherein G-1 treatment of mice with MS hypertension becomes higher in women than in men. 194,195
(no data on sex reported in the publication) decreased Studies using postmenopausal hypertension rat models
the release of proinflammatory cytokines and thus the have shown that premenopausal females had lower blood
severity of the disease. Similar results were reported pressure than age-matched males; however, with aging, the
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by Bodhankar and Offner, who analyzed the effect blood pressure increased significantly compared with that
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of the activation of ERs on the pathophysiology of in their male counterparts. 196,197 This finding supports the
MS in an animal model of experimental autoimmune assumption that sex hormones play a protective role in the
encephalomyelitis (EAE). They reported a protective vascular system. 198
function of G-1 on CNS infiltration, demyelination,
and axonal loss in the MS mouse model, highlighting Recent studies have suggested that GPER1 has a major
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the protective role of GPER1 in MS. Consistent with impact on vasodilatation and blood pressure regulation.
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these results, G-1 administration in demyelinated rats Compared with normotensive premenopausal women,
resulted in increased remyelination through enhanced low serum GPER1 levels are correlated with hypertension
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oligodendrocyte maturation in the corpus callosum. in postmenopausal women (Table 1). GPER1 is widely
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Analysis of the impact of GPER1 KO in a female mouse expressed in the cardiovascular system, which has
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model of EAE further confirmed that the E2-mediated already been demonstrated in cardiomyocytes, cardiac
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reduction of EAE is only partially mediated by GPER1 fibroblasts, coronary artery endothelial cells, and
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activation. However, Yates et al. exclusively reported coronary artery vascular smooth muscle cells. Therefore,
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an E2-induced reduction in EAE severity by GPER1 and GPER1 is involved in a plethora of varying physiological
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not by ERα, because GPER1 KO attenuated the beneficial functions, as previously described in the CNS and
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effects of E2 on EAE in a female mouse model of EAE. cardiovascular system. GPER1 activation affects
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203,204
Similarly, analyses of the influence of Vitamin D3 on diastolic function and positively influences cardiac
female EAE mice revealed preventive effects on clinical MS remodeling by preventing the proliferation of fibroblasts
signs, demyelination, and CNS lesions induced by GPER1, and mast cells through the inhibition of the cell cycle
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as these effects were abolished in GPER1 KO mice. genes cyclin B1 and CDK1. Besides these beneficial
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Besides its regulatory role in myelination, G-1-induced effects of GPER1, its genomic region on chromosome 7p22
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activation of GPER1 was shown to decrease oxidative has been linked to hypertension. A further indication
stress through the upregulation of excitatory amino acid of the involvement of GPER1 in pathophysiological
carrier 1 in rat glial cells. Mechanistically, the in vitro cardiovascular mechanisms was demonstrated by Liu
reduction of oxidative stress was mediated by GPER1- et al. in 2018, who reported the association of GPER1 with
sphingosine kinase 1–fibroblast growth factor 2–ERK1/2 hypertension as a protective factor in menopausal women,
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signaling. Although there are no data on the impact of but not in premenopausal women.
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nutraceuticals, such as EGCG, on MS, their role in GPER1 Studies using GPER1 KO rodents have elucidated the
activation and neuroinflammation (section 2.1) suggests GPER1-mediated physiological mechanisms underlying
that they are crucial in MS pathophysiology. Overall, vasodilatation. For instance, Tropea et al. showed
GPER1 may mediate some beneficial effects on MS in that GPER1 activation by G-1 induced NO-mediated
rodent models through its action on neuroinflammation, vasodilation in the uterine arteries of pregnant and non-
oxidative stress, and myelination (Figure 1). pregnant rats by modulating the NO/cyclic guanosine
Volume 4 Issue 1 (2025) 12 doi: 10.36922/gpd.4632