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Title: β3 Adrenergic Receptor Signaling in the Human Myometrium

Preterm labor leading to preterm birth is the leading cause of infant morbidity and mortality. Although β2 adrenergic agonists fail to provide adequate tocolysis, the expression of the β3 adrenergic receptor in myometrium and its unique signaling suggest a role for β3 agonist in the management of pr...

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Autores principales: Asif, Hazik, Barnett, Scott D., Buxton, Iain L. O.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8980516/
https://www.ncbi.nlm.nih.gov/pubmed/35380411
http://dx.doi.org/10.1007/s43032-022-00917-y
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author Asif, Hazik
Barnett, Scott D.
Buxton, Iain L. O.
author_facet Asif, Hazik
Barnett, Scott D.
Buxton, Iain L. O.
author_sort Asif, Hazik
collection PubMed
description Preterm labor leading to preterm birth is the leading cause of infant morbidity and mortality. Although β2 adrenergic agonists fail to provide adequate tocolysis, the expression of the β3 adrenergic receptor in myometrium and its unique signaling suggest a role for β3 agonist in the management of preterm labor. Western blot analysis showed that the β3 adrenergic receptor expression increased in human pregnancy myometrium compared to nonpregnant tissues (p < 0.0001). There was no difference in β3 adrenergic receptor expression throughout pregnancy (p > 0.05). The addition of the β3 agonist mirabegron in the tissue bath relaxed oxytocin contracted myometrium with an EC(50) of 41.5 µM. Relaxation was partially blocked by the addition of the eNOS blocker Nω-nitro-L-arginine, or the large conductance potassium channel blocker paxilline. Combination of Nω-nitro-L-arginine and paxilline prevented mirabegron-mediated relaxation. Imaging revealed that the β3 adrenergic receptors are expressed by both myocyte and microvascular endothelial cells isolated from human myometrium. Nitric oxide production measured by 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate revealed that mirabegron stimulated nitric oxide production in myometrial endothelial cells. These data suggest that both endothelial and smooth muscle cells contribute to relaxation through disparate signaling pathways. Repurposing of approved medications tested in human myometrium as uterine tocolytics can advance prevention of preterm birth. These data argue that further examination of β3 adrenergic receptor signaling in myometrium may reveal mirabegron as a useful tocolytic in combination tocolysis regimens.
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spelling pubmed-89805162022-04-05 Title: β3 Adrenergic Receptor Signaling in the Human Myometrium Asif, Hazik Barnett, Scott D. Buxton, Iain L. O. Reprod Sci Reproductive Biology: Original Article Preterm labor leading to preterm birth is the leading cause of infant morbidity and mortality. Although β2 adrenergic agonists fail to provide adequate tocolysis, the expression of the β3 adrenergic receptor in myometrium and its unique signaling suggest a role for β3 agonist in the management of preterm labor. Western blot analysis showed that the β3 adrenergic receptor expression increased in human pregnancy myometrium compared to nonpregnant tissues (p < 0.0001). There was no difference in β3 adrenergic receptor expression throughout pregnancy (p > 0.05). The addition of the β3 agonist mirabegron in the tissue bath relaxed oxytocin contracted myometrium with an EC(50) of 41.5 µM. Relaxation was partially blocked by the addition of the eNOS blocker Nω-nitro-L-arginine, or the large conductance potassium channel blocker paxilline. Combination of Nω-nitro-L-arginine and paxilline prevented mirabegron-mediated relaxation. Imaging revealed that the β3 adrenergic receptors are expressed by both myocyte and microvascular endothelial cells isolated from human myometrium. Nitric oxide production measured by 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate revealed that mirabegron stimulated nitric oxide production in myometrial endothelial cells. These data suggest that both endothelial and smooth muscle cells contribute to relaxation through disparate signaling pathways. Repurposing of approved medications tested in human myometrium as uterine tocolytics can advance prevention of preterm birth. These data argue that further examination of β3 adrenergic receptor signaling in myometrium may reveal mirabegron as a useful tocolytic in combination tocolysis regimens. Springer International Publishing 2022-04-04 /pmc/articles/PMC8980516/ /pubmed/35380411 http://dx.doi.org/10.1007/s43032-022-00917-y Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Reproductive Biology: Original Article
Asif, Hazik
Barnett, Scott D.
Buxton, Iain L. O.
Title: β3 Adrenergic Receptor Signaling in the Human Myometrium
title Title: β3 Adrenergic Receptor Signaling in the Human Myometrium
title_full Title: β3 Adrenergic Receptor Signaling in the Human Myometrium
title_fullStr Title: β3 Adrenergic Receptor Signaling in the Human Myometrium
title_full_unstemmed Title: β3 Adrenergic Receptor Signaling in the Human Myometrium
title_short Title: β3 Adrenergic Receptor Signaling in the Human Myometrium
title_sort title: β3 adrenergic receptor signaling in the human myometrium
topic Reproductive Biology: Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8980516/
https://www.ncbi.nlm.nih.gov/pubmed/35380411
http://dx.doi.org/10.1007/s43032-022-00917-y
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