| First Author | Yu Q | Year | 2019 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 39 |
| Issue | 3 | Pages | e91-e105 |
| PubMed ID | 30651001 | Mgi Jnum | J:292077 |
| Mgi Id | MGI:6443802 | Doi | 10.1161/ATVBAHA.118.312212 |
| Citation | Yu Q, et al. (2019) PI3Kgamma (Phosphoinositide 3-Kinase gamma) Regulates Vascular Smooth Muscle Cell Phenotypic Modulation and Neointimal Formation Through CREB (Cyclic AMP-Response Element Binding Protein)/YAP (Yes-Associated Protein) Signaling. Arterioscler Thromb Vasc Biol 39(3):e91-e105 |
| abstractText | Objective- Vascular smooth muscle cells (VSMCs) phenotype modulation is critical for the resolution of vascular injury. Genetic and pharmacological inhibition of PI3Kgamma (phosphoinositide 3-kinase gamma) exerts anti-inflammatory and protective effects in multiple cardiovascular diseases. This study investigated the role of PI3Kgamma 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 PI3Kgamma 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 SM22alpha, 2 differentiation markers of VSMCs. However, the injury-induced downregulation of calponin and SM22alpha was profoundly attenuated in PI3Kgamma(-/-) mice. Pharmacological inhibition and short hairpin RNA knockdown of PI3Kgamma (PI3Kgamma-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 PI3Kgamma-KD VSMCs. Moreover, established carotid artery ligation and chimeric mice models demonstrate that deletion of PI3Kgamma in naive PI3Kgamma(-/-) mice as well as in chimeric mice lacking PI3Kgamma either in bone marrow or vascular wall significantly reduced neointimal formation after injury. Conclusions- PI3Kgamma controls phenotypic modulation of VSMCs by regulating transcription factor CREB activation and YAP expression. Modulating PI3Kgamma signaling on local vascular wall may represent a new therapeutic approach to treat proliferative vascular disease. |
