title: Notch transcriptional control of vascular smooth muscle regulatory gene expression and function.
abstract: Notch receptors and ligands mediate heterotypic cell signaling that is required for normal vascular development. Dysregulation of select Notch receptors in mouse vascular smooth muscle (VSM) and in genetic human syndromes causes functional impairment in some regional circulations, the mechanistic basis of which is undefined. In this study, we used a dominant-negative Mastermind-like (DNMAML1) to block signaling through all Notch receptors specifically in VSM to more broadly test a functional role for this pathway in vivo. Mutant DNMAML1-expressing mice exhibited blunted blood pressure responses to vasoconstrictors, and their aortic, femoral, and mesenteric arteries had reduced contractile responses to agonists and depolarization in vitro. The mutant arteries had significant and specific reduction in the expression and activity of myosin light chain kinase (MLCK), a primary regulator of VSM force production. Conversely, activated Notch signaling in VSM cells induced endogenous MLCK transcript levels. We identified MLCK as a direct target of activated Notch receptor as demonstrated by an evolutionarily conserved Notch-responsive element within the MLCK promoter that binds the Notch receptor complex and is required for transcriptional activity. We conclude that Notch signaling through the transcriptional control of key regulatory proteins is required for contractile responses of mature VSM. Genetic or pharmacological manipulation of Notch signaling is a potential strategy for modulating arterial function in human disease.
authors.affiliation: Department of Medicine, Case Cardiovascular Research Institute, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Sanchita
authors.initials: S
authors.lastname: Basu
authors.forename: Dinesh Kumar
authors.initials: DK
authors.lastname: Srinivasan
authors.forename: Ke
authors.initials: K
authors.lastname: Yang
authors.forename: Hema
authors.initials: H
authors.lastname: Raina
authors.forename: Suhanti
authors.initials: S
authors.lastname: Banerjee
authors.forename: Rongli
authors.initials: R
authors.lastname: Zhang
authors.forename: Steven A
authors.initials: SA
authors.lastname: Fisher
authors.forename: Aaron
authors.initials: A
authors.lastname: Proweller
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009119:Muscle Contraction / Q000235:genetics; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009219:Myosin-Light-Chain Kinase / Q000096:biosynthesis / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D014652:Vascular Diseases / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D014661:Vasoconstriction / Q000235:genetics
chemical_list: C486455:Maml1 protein, mouse; D009124:Muscle Proteins; D009687:Nuclear Proteins; D051880:Receptors, Notch; D014157:Transcription Factors; D009219:Myosin-Light-Chain Kinase