Vascularsmoothmusclecell(VSMC)phenotypicmodulationiscentraltotheetiologiesofmultiplevascularwall diseases. In post-angioplasty restenosis and atherosclerosis, VSMCs acquire a proliferative/migratory phenotype leading to neointima formation. In contrast, hypertension islargely caused by increased vascular resistancethatisattributedtoexaggeratedVSMCcontractionandvascularremodeling.Identificationofthekey players that regulate VSMC proliferation and contraction is critical for further understanding of the underlying mechanismsofVSMC-drivenvascularwalldiseasesandalsofordevelopingnoveltherapeuticapproaches.We havepreviouslydemonstratedthatthetranscriptionco-factoryes-associatedprotein1(YAP1)promotesVSMC proliferation. Yet, the role and underlying mechanisms of YAP1 in neointima formation in vivo remain unclear. Furthermore, recent genome-wide association studies (GWAS) have identified a loss-of-function single nucleotide polymorphism (SNP) in YAP1 gene locus that was unexpectedly associated with lower blood pressure,suggestinganovelroleofYAP1inbloodpressureregulation.Theoverarchinggoalofthisproposalis to determine the role of YAP1 in regulating both VSMC proliferation and contraction/hypertension. Novel preliminary data in this proposal include 1) YAP1 expression is upregulated after arterial injury and correlates withVSMCproliferationinvivo,2)YAP1,inassociationwithTEAdomaintranscriptionfactor1(TEAD1),induces platelet-derivedgrowthfactorreceptorbeta(PDGFRb?),aputativenovelYAP1targetgenethatregulatesVSMC phenotype,3)SM-specificYap1knockoutmiceexhibitahypotensivephenotypeandanattenuatedresponseto vasoconstrictorsinisolatedvessels,and4)silencingYAP1inVSMCsinhibitedproteinkinaseCalpha(PRKCa?) signaling and impaired actin polymerization, which are key for VSMC contraction.
Three specific aims are proposedtotestthecentralhypothesisthatYAP1inducesVSMCproliferationandcontractiontodriveneointima formation and hypertension, respectively.
K99 Aim 1. Test the hypothesis that YAP1 induces PDGFRb? to promote VSMC proliferation and enhance injury-induced neointima formation in vivo.
R00 Aim 2. Test the hypothesis that YAP1 activates PRKCa? signaling and promotes actin polymerization to enhance VSMC contraction.
R00 Aim3. TestthehypothesisthatVSMC-expressedYAP1underliesexperimentalhypertension. CompletionoftheproposedstudieswillprovidenovelinsightsintothemechanismsregulatingVSMCphenotypic modulationandbloodpressureregulationandwilldetermineifinhibitingYAP1isanattractivenoveltherapeutic strategy for ameliorating both occlusive vascular diseases and hypertension. Additional conceptual and experimental training in hypertension-related researchduring the K99 phase will helptheapplicant pursue an independentcareerandtransformthisproposalintoanR01applicationduringtheR00phase.
Cardiovascular disease remains the number one cause of death in the United States and worldwide. The proposed study utilizes a translational approach incorporating the use of transgenic animal models, advanced smoothmusclecellculturetechniques,pharmacologicalstrategiesandcollaborationswithleadersinthefieldto rigorously test the hypothesis that the transcription co-factor yes-associated protein 1 induces smooth muscle proliferationandcontractiontodrivevascularwallthickeningandhypertension,respectively.Completionofthe proposed studies will provide novel insights into the mechanisms regulating vascular wall diseases and will determine if inhibiting YAP1 isan attractivenoveltherapeutic strategy forameliorating bothocclusive vascular diseasesandhypertension.
