Proliferation of human primary vascular smooth muscle cells depends on serum response factor.

Smoothmusclecells(SMCs)canswitchbetweenadifferentiated/contractileandanalternative proliferativephenotype.Thetranscriptionfactorserumresponsefactor(SRF)hasbeenimplicatedinthe regulation ofgeneexpressionprofilesdeterminingbothphenotypes.Whereasstrongevidenceexistsfor a roleofSRFinSMCdifferentiation,thecontributionofSRFtoSMCproliferationislesswelldefined.For primaryhumanvascularSMCsinparticular,existingdataarenon-conclusive.TostudySRFfunctionsin primaryhumanvascularSMCs,weusedansiRNAapproach.siRNA-mediated SRF suppressionaffected the expressionofestablishedSRFtargetgenessuchassmoothmuscle a-actin(ACTA2) or SM22a (TAGLN) anddecreasedbothF-actinformationandcellmigration.Furthermore,SRFknockdowncaused a cell-cyclearrestinG1associatedwithreducedhyperphosphorylatedpRB,cyclinAandSKP2levels, and increasedp27kip1 (CDKN1B)proteinlevels.SRF-depletedcellsexpressedsenescence-associated bgalactosidaseindicatinganirreversibleG1arrest.siRNA-mediatedsuppressionof SKP2 triggered senescencetoasimilarextentasSRFdepletion,indicatingthatSRFknockdown-inducedsenescence may bedependentonadecreaseinSKP2.Thus,SRFisanessentialregulatorofprimaryhumanvascular SMC proliferationandsenescence.InterferingwithSRFfunctionmaythereforebeapromisingstrategy for thetreatmentofhyperproliferativeSMCdisorderssuchasatherosclerosisandin-stentrestenosis.