title: Smoothelin-like 1 protein regulates myosin phosphatase-targeting subunit 1 expression during sexual development and pregnancy.
abstract: Pregnancy coordinately alters the contractile properties of both vascular and uterine smooth muscles reducing systemic blood pressure and maintaining uterine relaxation. The precise molecular mechanisms underlying these pregnancy-induced adaptations have yet to be fully defined but are likely to involve changes in the expression of proteins regulating myosin phosphorylation. Here we show that smoothelin like protein 1 (SMTNL1) is a key factor governing sexual development and pregnancy induced adaptations in smooth and striated muscle. A primary target gene of SMTNL1 in these muscles is myosin phosphatase-targeting subunit 1 (MYPT1). Deletion of SMTNL1 increases expression of MYPT1 30-40-fold in neonates and during development expression of both SMTNL1 and MYPT1 increases over 20-fold. Pregnancy also regulates SMTNL1 and MYPT1 expression, and deletion SMTNL1 greatly exaggerates expression of MYPT1 in vascular smooth muscle, producing a profound reduction in force development in response to phenylephrine as well as sensitizing the muscle to acetylcholine. We also show that MYPT1 is expressed in Type2a muscle fibers in mice and humans and its expression is regulated during pregnancy, suggesting unrecognized roles in mediating skeletal muscle plasticity in both species. Our findings define a new conserved pathway in which sexual development and pregnancy mediate smooth and striated muscle adaptations through SMTNL1 and MYPT1.
authors.affiliation: Department of Pharmacology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Beata
authors.initials: B
authors.lastname: Lontay
authors.forename: Khaldon
authors.initials: K
authors.lastname: Bodoor
authors.forename: Douglas H
authors.initials: DH
authors.lastname: Weitzel
authors.forename: David
authors.initials: D
authors.lastname: Loiselle
authors.forename: Christopher
authors.initials: C
authors.lastname: Fortner
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Lengyel
authors.forename: Donghai
authors.initials: D
authors.lastname: Zheng
authors.forename: James
authors.initials: J
authors.lastname: Devente
authors.forename: Robert
authors.initials: R
authors.lastname: Hickner
authors.forename: Timothy A J
authors.initials: TA
authors.lastname: Haystead
mesh_terms: D000328:Adult; D000818:Animals; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D018613:Microscopy, Confocal; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009130:Muscle, Smooth / Q000378:metabolism*; D054792:Muscle, Striated / Q000378:metabolism*; D009219:Myosin-Light-Chain Kinase / Q000235:genetics / Q000378:metabolism*; D043263:Myosin-Light-Chain Phosphatase; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011247:Pregnancy; D011485:Protein Binding / Q000235:genetics / Q000502:physiology; D021381:Protein Transport / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014599:Uterus / Q000378:metabolism; D000096985:Calponins
chemical_list: D009124:Muscle Proteins; D009219:Myosin-Light-Chain Kinase; D043263:Myosin-Light-Chain Phosphatase; D010750:Phosphoproteins; C491838:SMTNL1 protein, mouse; D000096985:Calponins; C510645:Ppp1r12a protein, mouse