Nidogen-2 Maintains the Contractile Phenotype of Vascular Smooth Muscle Cells and Prevents Neointima Formation via Bridging Jagged1-Notch3 Signaling
| Autor: | Qinghua Cui, Jin-Peng Sun, Yiting Jia, Yi Fu, Nan Xie, Fang Yu, Guizhen Zhao, Wei Kong, Ma Zihan, Baihui Ma, Weihao Li, Yuan Zhou, Chenfeng Mao |
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| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine Neointima Vascular smooth muscle Bridging (networking) Vascular homeostasis 030204 cardiovascular system & hematology Muscle Smooth Vascular Extracellular matrix Mice 03 medical and health sciences 0302 clinical medicine Physiology (medical) Animals Humans Medicine Receptor Notch3 Mice Knockout business.industry Calcium-Binding Proteins Contractile phenotype Cell biology Phenotype 030104 developmental biology cardiovascular system Nidogen-2 Cardiology and Cardiovascular Medicine business Cell Adhesion Molecules Jagged-1 Protein |
| Zdroj: | Circulation. 144:1244-1261 |
| ISSN: | 1524-4539 0009-7322 |
| Popis: | Background: How the extracellular matrix (ECM) microenvironment modulates the contractile phenotype of vascular smooth muscle cells (VSMCs) and confers vascular homeostasis remains elusive. Methods: To explore the key ECM proteins in the maintenance of the contractile phenotype of VSMCs, we applied protein-protein interaction network analysis to explore novel ECM proteins associated with the VSMC phenotype. By combining in vitro and in vivo genetic mice vascular injury models, we identified nidogen-2, a basement membrane glycoprotein, as a key ECM protein for maintenance of vascular smooth muscle cell identity. Results: We collected a VSMC phenotype–related gene dataset by using Gene Ontology annotation combined with a literature search. A computational analysis of protein-protein interactions between ECM protein genes and the genes from the VSMC phenotype–related gene dataset revealed the candidate gene nidogen-2, a basement membrane glycoprotein involved in regulation of the VSMC phenotype. Indeed, nidogen-2–deficient VSMCs exhibited loss of contractile phenotype in vitro, and compared with wild-type mice, nidogen-2 –/ – mice showed aggravated post–wire injury neointima formation of carotid arteries. Further bioinformatics analysis, coimmunoprecipitation assays, and luciferase assays revealed that nidogen-2 specifically interacted with Jagged1, a conventional Notch ligand. Nidogen-2 maintained the VSMC contractile phenotype via Jagged1-Notch3 signaling but not Notch1 or Notch2 signaling. Nidogen-2 enhanced Jagged1 and Notch3 interaction and subsequent Notch3 activation. Reciprocally, Jagged1 and Notch3 interaction, signaling activation, and Jagged1-triggered VSMC differentiation were significantly repressed in nidogen-2–deficient VSMCs. In accordance, the suppressive effect of Jagged1 overexpression on neointima formation was attenuated in nidogen-2 –/– mice compared with wild-type mice. Conclusions: Nidogen-2 maintains the contractile phenotype of VSMCs through Jagged1-Notch3 signaling in vitro and in vivo. Nidogen-2 is required for Jagged1-Notch3 signaling. |
| Databáze: | OpenAIRE |
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