title: Notch3 signaling in vascular smooth muscle cells induces c-FLIP expression via ERK/MAPK activation. Resistance to Fas ligand-induced apoptosis.
abstract: Mutations in the Notch3 receptor result in the cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephelopathy (CADASIL) syndrome, a heritable arteriopathy predisposing to early onset stroke. Based upon clinical evidence that CADASIL arteriopathy results in degeneration and loss of vascular smooth muscle cells (VSMC) from the arterial wall, we postulated that Notch3 signaling is a critical determinant of VSMC survival. We initially established that both transient and constitutive Notch3 signaling promoted VSMC survival in response to the proapoptotic Fas ligand (FasL). Resistance to FasL-induced apoptosis was associated with the induction of c-FLIP, a primary inhibitor of the FasL signaling pathway. We determined that Notch3's regulation of c-FLIP was independent of the activity of the classical DNA-binding protein, RBP-Jk, but dependent upon cross-talk activation of the ERK/MAPK pathway. We extended our observations to the in vivo context by determining a coordinate regulation of Notch3 and c-FLIP within the arterial wall in response to injury. Furthermore, we defined that expression levels of Notch3 and c-FLIP are coordinately up-regulated within the neointima of remodeled arteries. Taken together, these findings provide initial evidence that Notch3 signaling may be a critical determinant of VSMC survival and vascular structure by modulating the expression of downstream mediators of apoptosis via signaling cross-talk with the ERK/MAPK pathway.
authors.affiliation: Cardiovascular Research Institute, Morehouse School of Medicine, Atlanta, Georgia 30310, USA.
authors.forename: Wenli
authors.initials: W
authors.lastname: Wang
authors.forename: Chengyu Z
authors.initials: CZ
authors.lastname: Prince
authors.forename: Yongshan
authors.initials: Y
authors.lastname: Mou
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Pollman
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002339:Carotid Arteries / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism*; D002470:Cell Survival; D002478:Cells, Cultured; D015536:Down-Regulation; D004789:Enzyme Activation; D053222:Fas Ligand Protein; D047908:Intracellular Signaling Peptides and Proteins; D020935:MAP Kinase Signaling System; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009130:Muscle, Smooth / Q000166:cytology / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface; D012190:Retroviridae / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins; D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D020928:Mitogen-Activated Protein Kinases