气候变化领域集成服务门户(CCPortal): Progesterone receptor isoform B regulates the Oxtr-Plcl2-Trpc3 pathway to suppress uterine contractility

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DOI	10.1073/PNAS.2011643118
	Progesterone receptor isoform B regulates the Oxtr-Plcl2-Trpc3 pathway to suppress uterine contractility
	Peavey M.C.; Wu S.-P.; Li R.; Liu J.; Emery O.M.; Wang T.; Zhou L.; Wetendorf M.; Yallampalli C.; Gibbons W.E.; Lydon J.P.; DeMayo F.J.
发表日期	2021
ISSN	00278424
卷号	118 期号:11
英文摘要	Uterine contractile dysfunction leads to pregnancy complications such as preterm birth and labor dystocia. In humans, it is hypothesized that progesterone receptor isoform PGR-B promotes a relaxed state of the myometrium, and PGR-A facilitates uterine contraction. This hypothesis was tested in vivo using transgenic mouse models that overexpress PGR-A or PGR-B in smooth muscle cells. Elevated PGR-B abundance results in a marked increase in gestational length compared to control mice (21.1 versus 19.1 d respectively, P < 0.05). In both ex vivo and in vivo experiments, PGR-B overexpression leads to prolonged labor, a significant decrease in uterine contractility, and a high incidence of labor dystocia. Conversely, PGR-A overexpression leads to an increase in uterine contractility without a change in gestational length. Uterine RNA sequencing at midpregnancy identified 1,174 isoform-specific downstream targets and 424 genes that are commonly regulated by both PGR isoforms. Gene signature analyses further reveal PGR-B for muscle relaxation and PGR-A being proinflammatory. Elevated PGR-B abundance reduces Oxtr and Trpc3 and increases Plcl2 expression, which manifests a genetic profile of compromised oxytocin signaling. Functionally, both endogenous PLCL2 and its paralog PLCL1 can attenuate uterine muscle cell contraction in a CRISPRa-based assay system. These findings provide in vivo support that PGR isoform levels determine distinct transcriptomic landscapes and pathways in myometrial function and labor, which may help further the understanding of abnormal uterine function in the clinical setting. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Contractility; Labor; Myometrium; Parturition; Progesterone receptor isoform
语种	英语
scopus关键词	oxytocin; oxytocin receptor; phospholipase C; PLCL1 protein; PLCL2 protein; progesterone receptor A; progesterone receptor B; transient receptor potential channel 3; unclassified drug; animal experiment; animal model; animal tissue; Article; clustered regularly interspaced short palindromic repeat; controlled study; dystocia; ex vivo study; female; gene; gene overexpression; gestation period; human; human tissue; in vivo study; inflammation; labor; mouse; muscle relaxation; myometrium; nonhuman; Oxtr gene; Plcl2 gene; pregnancy; priority journal; RNA sequencing; Trpc3 gene; uterus contractility
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/181182
作者单位	Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill, NC 27599, United States; Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, United States; Integrative Bioinformatic Support Group, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, United States; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, United States; Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX 77030, United States
推荐引用方式 GB/T 7714	Peavey M.C.,Wu S.-P.,Li R.,et al. Progesterone receptor isoform B regulates the Oxtr-Plcl2-Trpc3 pathway to suppress uterine contractility[J],2021,118(11).
APA	Peavey M.C..,Wu S.-P..,Li R..,Liu J..,Emery O.M..,...&DeMayo F.J..(2021).Progesterone receptor isoform B regulates the Oxtr-Plcl2-Trpc3 pathway to suppress uterine contractility.Proceedings of the National Academy of Sciences of the United States of America,118(11).
MLA	Peavey M.C.,et al."Progesterone receptor isoform B regulates the Oxtr-Plcl2-Trpc3 pathway to suppress uterine contractility".Proceedings of the National Academy of Sciences of the United States of America 118.11(2021).