G protein estrogen receptor as a potential therapeutic target in Raynaud’s phenomenon
Exaggerated cold-induced vasoconstriction can precipitate a pathogenesis called Raynaud’s phenomenon (RP). Interestingly, RP is significantly more prevalent in females than age-matched men, highlighting the potential implication of 17β-estradiol (E2) in the etio-pathogenesis of this disease. Indeed,...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-11-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.1061374/full |
| _version_ | 1797988953954975744 |
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| author | Manal Fardoun Stefania Mondello Firas Kobeissy Ali H. Eid |
| author_facet | Manal Fardoun Stefania Mondello Firas Kobeissy Ali H. Eid |
| author_sort | Manal Fardoun |
| collection | DOAJ |
| description | Exaggerated cold-induced vasoconstriction can precipitate a pathogenesis called Raynaud’s phenomenon (RP). Interestingly, RP is significantly more prevalent in females than age-matched men, highlighting the potential implication of 17β-estradiol (E2) in the etio-pathogenesis of this disease. Indeed, we have previously reported that E2 stimulates the expression of vascular alpha 2C-adrenoceptors (α2C-AR), the sole mediator of cold-induced constriction of cutaneous arterioles. This induced expression occurs through the cyclic adenosine monophosphate → exchange protein activated by cAMP→ Ras-related protein 1→ c-Jun N-terminal kinase→ activator protein-1 (cAMP/Epac/Rap/JNK/AP-1 pathway). On the basis that estrogen-induced rapid cAMP accumulation and JNK activation occurs so rapidly we hypothesized that a non-classic, plasma membrane estrogen receptor was the mediator. We then showed that an impermeable form of E2, namely E2:BSA, mimics E2 effects suggesting a role for the membranous G-protein coupled estrogen receptor (GPER) in E2-induced α2C-AR expression. Our current working hypothesis and unpublished observations further cement this finding, as G1, a GPER agonist, mimics while G15, a GPER antagonist, abrogates estrogen’s effect on the expression of vascular α2C-AR. These, and other observations, highlight the potential of GPER as a tractable target in the management of RP, particularly in pre-menopausal women. |
| first_indexed | 2024-04-11T08:11:32Z |
| format | Article |
| id | doaj.art-690387c8959c48ffba83a268f85e6b07 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-11T08:11:32Z |
| publishDate | 2022-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-690387c8959c48ffba83a268f85e6b072022-12-22T04:35:19ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-11-011310.3389/fphar.2022.10613741061374G protein estrogen receptor as a potential therapeutic target in Raynaud’s phenomenonManal Fardoun0Stefania Mondello1Firas Kobeissy2Ali H. Eid3Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, LebanonDepartment of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, ItalyDepartment of Emergency Medicine, University of Florida, Gainesville, FL, United StatesDepartment of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha, QatarExaggerated cold-induced vasoconstriction can precipitate a pathogenesis called Raynaud’s phenomenon (RP). Interestingly, RP is significantly more prevalent in females than age-matched men, highlighting the potential implication of 17β-estradiol (E2) in the etio-pathogenesis of this disease. Indeed, we have previously reported that E2 stimulates the expression of vascular alpha 2C-adrenoceptors (α2C-AR), the sole mediator of cold-induced constriction of cutaneous arterioles. This induced expression occurs through the cyclic adenosine monophosphate → exchange protein activated by cAMP→ Ras-related protein 1→ c-Jun N-terminal kinase→ activator protein-1 (cAMP/Epac/Rap/JNK/AP-1 pathway). On the basis that estrogen-induced rapid cAMP accumulation and JNK activation occurs so rapidly we hypothesized that a non-classic, plasma membrane estrogen receptor was the mediator. We then showed that an impermeable form of E2, namely E2:BSA, mimics E2 effects suggesting a role for the membranous G-protein coupled estrogen receptor (GPER) in E2-induced α2C-AR expression. Our current working hypothesis and unpublished observations further cement this finding, as G1, a GPER agonist, mimics while G15, a GPER antagonist, abrogates estrogen’s effect on the expression of vascular α2C-AR. These, and other observations, highlight the potential of GPER as a tractable target in the management of RP, particularly in pre-menopausal women.https://www.frontiersin.org/articles/10.3389/fphar.2022.1061374/fullraynaud’s phenomenonestrogenVSMCalpha 2C adrenoceptorGPERvasoconstriction |
| spellingShingle | Manal Fardoun Stefania Mondello Firas Kobeissy Ali H. Eid G protein estrogen receptor as a potential therapeutic target in Raynaud’s phenomenon Frontiers in Pharmacology raynaud’s phenomenon estrogen VSMC alpha 2C adrenoceptor GPER vasoconstriction |
| title | G protein estrogen receptor as a potential therapeutic target in Raynaud’s phenomenon |
| title_full | G protein estrogen receptor as a potential therapeutic target in Raynaud’s phenomenon |
| title_fullStr | G protein estrogen receptor as a potential therapeutic target in Raynaud’s phenomenon |
| title_full_unstemmed | G protein estrogen receptor as a potential therapeutic target in Raynaud’s phenomenon |
| title_short | G protein estrogen receptor as a potential therapeutic target in Raynaud’s phenomenon |
| title_sort | g protein estrogen receptor as a potential therapeutic target in raynaud s phenomenon |
| topic | raynaud’s phenomenon estrogen VSMC alpha 2C adrenoceptor GPER vasoconstriction |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.1061374/full |
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