PI3K? (Phosphoinositide 3-Kinase ?) Regulates Vascular Smooth Muscle Cell Phenotypic Modulation and Neointimal Formation Through CREB (Cyclic AMP-Response Element Binding Protein)/YAP (Yes-Associated Protein) Signaling.

ABSTRACT: Objective- Vascular smooth muscle cells (VSMCs) phenotype modulation is critical for the resolution of vascular injury. Genetic and pharmacological inhibition of PI3K? (phosphoinositide 3-kinase ?) exerts anti-inflammatory and protective effects in multiple cardiovascular diseases. This study investigated the role of PI3K? and its downstream effector molecules in the regulation of VSMC phenotypic modulation and neointimal formation in response to vascular injury. Approach and Results- Increased expression of PI3K? was found in injured vessel wall as well in cultured, serum-activated wild-type VSMCs, accompanied by a reduction in the expression of calponin and SM22?, 2 differentiation markers of VSMCs. However, the injury-induced downregulation of calponin and SM22? was profoundly attenuated in PI3K?-/- mice. Pharmacological inhibition and short hairpin RNA knockdown of PI3K? (PI3K?-KD) markedly attenuated YAP (Yes-associated protein) expression and CREB (cyclic AMP-response element binding protein) activation but improved the downregulation of differentiation genes in cultured VSMCs accompanied by reduced cell proliferation and migration. Mechanistically, activated CREB upregulated YAP transcriptional expression through binding to its promoter. Ectopic expression of YAP strikingly repressed the expression of differentiation genes even in PI3K?-KD VSMCs. Moreover, established carotid artery ligation and chimeric mice models demonstrate that deletion of PI3K? in naïve PI3K?-/- mice as well as in chimeric mice lacking PI3K? either in bone marrow or vascular wall significantly reduced neointimal formation after injury. Conclusions- PI3K? controls phenotypic modulation of VSMCs by regulating transcription factor CREB activation and YAP expression. Modulating PI3K? signaling on local vascular wall may represent a new therapeutic approach to treat proliferative vascular disease.

SUBMITTER: Yu Q 

PROVIDER: S-EPMC6393180 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature