GPCRs in context: sexual dimorphism in the cardiovascular system

Mouat, Margaret A; Coleman, James L.; Smith, Nicola J.

doi:10.1111/bph.14160

Cited by 20 publications

(21 citation statements)

References 123 publications

(172 reference statements)

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“…Mice of both sexes were included in the study as it has been previously shown that deletion of Gpr37L1 has sexually dimorphic effects in mice ( Coleman et al, 2018 ). It is becoming increasingly obvious that males and females utilize different integrated physiological mechanisms to buffer and maintain cardiovascular homeostasis ( Hart et al, 2009 ; Mouat et al, 2018 ), thus it is important to investigate how mechanisms may differ between the sexes. The mechanism by which GPR37L1 effects change in the cardiovascular system is unclear, though we propose it interacts either directly or indirectly with central cardiovascular control regions.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to these effects in the brain, GPR37L1 has a reported role in maintaining blood pressure homeostasis ( Min et al, 2010 ; Coleman et al, 2018 ; Zheng et al, 2018 ), and may represent a potential drug target for the treatment of hypertension ( Smith, 2015 ). Supporting this, the closest non-orphan relative of GPR37L1 by phylogeny is the endothelin B receptor ( Valdenaire et al, 1998 ), which is known to have cardiovascular effects ( Mouat et al, 2018 ). In addition, GPR37L1 itself is encoded within a renin blood pressure quantitative trait locus, specifically in a sub-region that promotes high blood pressure in rats ( Flister et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

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Deletion of Orphan G Protein-Coupled Receptor GPR37L1 in Mice Alters Cardiovascular Homeostasis in a Sex-Specific Manner

et al. 2021

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GPR37L1 is a family A orphan G protein-coupled receptor (GPCR) with a putative role in blood pressure regulation and cardioprotection. In mice, genetic ablation of Gpr37l1 causes sex-dependent effects; female mice lacking Gpr37l1 (GPR37L1−/−) have a modest but significant elevation in blood pressure, while male GPR37L1−/− mice are more susceptible to cardiovascular dysfunction following angiotensin II-induced hypertension. Given that this receptor is highly expressed in the brain, we hypothesize that the cardiovascular phenotype of GPR37L1−/− mice is due to changes in autonomic regulation of blood pressure and heart rate. To investigate this, radiotelemetry was employed to characterize baseline cardiovascular variables in GPR37L1−/− mice of both sexes compared to wildtype controls, followed by power spectral analysis to quantify short-term fluctuations in blood pressure and heart rate attributable to alterations in autonomic homeostatic mechanisms. Additionally, pharmacological ganglionic blockade was performed to determine vasomotor tone, and environmental stress tests were used to assess whether cardiovascular reactivity was altered in GPR37L1−/− mice. We observed that mean arterial pressure was significantly lower in female GPR37L1−/− mice compared to wildtype counterparts, but was unchanged in male GPR37L1−/− mice. GPR37L1−/− genotype had a statistically significant positive chronotropic effect on heart rate across both sexes when analyzed by two-way ANOVA. Power spectral analysis of these data revealed a reduction in power in the heart rate spectrum between 0.5 and 3 Hz in female GPR37L1−/− mice during the diurnal active period, which indicates that GPR37L1−/− mice may have impaired cardiac vagal drive. GPR37L1−/− mice of both sexes also exhibited attenuated depressor responses to ganglionic blockade with pentolinium, indicating that GPR37L1 is involved in maintaining sympathetic vasomotor tone. Interestingly, when these mice were subjected to aversive and appetitive behavioral stressors, the female GPR37L1−/− mice exhibited an attenuation of cardiovascular reactivity to aversive, but not appetitive, environmental stimuli. Together, these results suggest that loss of GPR37L1 affects autonomic maintenance of blood pressure, giving rise to sex-specific cardiovascular changes in GPR37L1−/− mice.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Deletion of Orphan G Protein-Coupled Receptor GPR37L1 in Mice Alters Cardiovascular Homeostasis in a Sex-Specific Manner

et al. 2021

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“…It would be interesting to clarify if there exist hormone independent differences in immune cell GPER1 levels between males and females, or if sex-dependent differences in estrogen levels are critical, although both phenomena could be important in different clinical conditions. Sex related differences in the expression of several other GPCRs have already been described and have been related to sex dimorphism in cardiovascular diseases and stress responses ( 97 , 98 ).…”

Section: Future Perspectives In Gper1 Immunity-related Researchmentioning

confidence: 97%

G Protein-Coupled Estrogen Receptor in Immune Cells and Its Role in Immune-Related Diseases

2020

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G protein-coupled estrogen receptor 1 (GPER1), is a functional estrogen receptor involved in estrogen related actions on several systems including processes of the nervous, reproductive, metabolic, cardiovascular, and immune system. Regarding the latter, GPER is expressed in peripheral B and T lymphocytes as well as in monocytes, eosinophils, and neutrophils. Several studies have implicated GPER in immune-mediated diseases like multiple sclerosis, Parkinson’s disease, and atherosclerosis-related inflammation, while a recent report suggests that its deletion could be responsible for a form of familial immunodeficiency. It has also been suggested that it is a key regulator of immune-mediated events in breast, pancreatic, prostate, and hepatocellular cancer as well as in melanoma. GPER has been also reported to interact with classic ER-alpha or its splice variants in order to modify immune functions. This review aims to present current knowledge relating GPER to immune functions, the cellular and signaling pathways involved, as well as the potential clinical implications of GPER modulation in immune-related diseases.

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“…Sexual differentiation starts during pre-natal life and continues throughout the life-span [69]. Relevantly, drug metabolism is influenced by sex–gender and age [70], as well as the activity of some inotropic and metabotropic receptors [71].…”

Section: Rulesmentioning

confidence: 99%

Sex-Gender Variable: Methodological Recommendations for Increasing Scientific Value of Clinical Studies

Franconi¹,

Campesi

Colombo

et al. 2019

Cells

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There is a clear sex–gender gap in the prevention and occurrence of diseases, and in the outcomes and treatments, which is relevant to women in the majority of cases. Attitudes concerning the enrollment of women in randomized clinical trials have changed over recent years. Despite this change, a gap still exists. This gap is linked to biological factors (sex) and psycho-social, cultural, and environmental factors (gender). These multidimensional, entangled, and interactive factors may influence the pharmacological response. Despite the fact that regulatory authorities recognize the importance of sex and gender, there is a paucity of research focusing on the racial/ethnic, socio-economic, psycho-social, and environmental factors that perpetuate disparities. Research and clinical practice must incorporate all of these factors to arrive at an intersectional and system-scenario perspective. We advocate for scientifically rigorous evaluations of the interplay between sex and gender as key factors in performing clinical trials, which are more adherent to real-life. This review proposes a set of 12 rules to improve clinical research for integrating sex–gender into clinical trials.

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GPCRs in context: sexual dimorphism in the cardiovascular system

Abstract: This article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.21/issuetoc.

Cited by 20 publications

References 123 publications

Deletion of Orphan G Protein-Coupled Receptor GPR37L1 in Mice Alters Cardiovascular Homeostasis in a Sex-Specific Manner

Deletion of Orphan G Protein-Coupled Receptor GPR37L1 in Mice Alters Cardiovascular Homeostasis in a Sex-Specific Manner

G Protein-Coupled Estrogen Receptor in Immune Cells and Its Role in Immune-Related Diseases

Sex-Gender Variable: Methodological Recommendations for Increasing Scientific Value of Clinical Studies

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