title: Differential Regulation of NOTCH2 and NOTCH3 Contribute to Their Unique Functions in Vascular Smooth Muscle Cells.
abstract: Notch signaling is a key regulator of vascular smooth muscle cell (VSMC) phenotypes, including differentiation, proliferation, and cell survival. However, the exact contribution of the individual Notch receptors has not been thoroughly delineated. In this study, we identify unique roles for NOTCH2 and NOTCH3 in regulating proliferation and cell survival in cultured VSMCs. Our results indicate that NOTCH2 inhibits PDGF-B-dependent proliferation and its expression is decreased by PDGF-B. In contrast, NOTCH3 promotes proliferation and receptor expression is increased by PDGF-B. Additionally, data show that NOTCH3, but not NOTCH2 protects VSMCs from apoptosis and apoptosis mediators degrade NOTCH3 protein. We identified three pro-survival genes specifically regulated by NOTCH3 in cultured VSMCs and in mouse aortas. This regulation is mediated through MAP kinase signaling, which we demonstrate can be activated by NOTCH3, but not NOTCH2. Overall, this study highlights discrete roles for NOTCH2 and NOTCH3 in VSMCs and connects these roles to specific upstream regulators that control their expression.
authors.affiliation: From the Center for Cardiovascular and Pulmonary Research, and The Heart Center at Nationwide Children's Hospital, and the Department of Pediatrics, The Ohio State University, Columbus, Ohio 43205.
authors.forename: Jeremy T
authors.initials: JT
authors.lastname: Baeten
authors.affiliation: From the Center for Cardiovascular and Pulmonary Research, and The Heart Center at Nationwide Children's Hospital, and the Department of Pediatrics, The Ohio State University, Columbus, Ohio 43205 brenda.lilly@nationwidechildrens.org.
authors.forename: Brenda
authors.initials: B
authors.lastname: Lilly
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D051883:Receptor, Notch2 / Q000235:genetics / Q000378:metabolism*; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C499374:NOTCH3 protein, human; C499373:Notch3 protein, mouse; D051883:Receptor, Notch2; D000071656:Receptor, Notch3; D051880:Receptors, Notch
keywords: Notch receptor; apoptosis; differentiation; mitogen-activated protein kinase (MAPK); proliferation; vascular smooth muscle cells