The Jagged/Notch signaling pathways control cell fate and differentiation, and their dysfunction is associated with human pathologies involving cardiovascular abnormalities. Mutations in the human Jagged1 gene cause the Alagille syndrome, a genetic disease causing cardiac abnormalities, and mutations in the Notch3 receptor have been found in CADASIL, a condition characterized by strokes and vascular dementia. Thus, components of the Notch pathway are important for maintenance of the cardiovasculature in the adult. Null mutations of Jagged/Notch genes in the mouse have been instrumental in showing the developmental requirement of these genes for cardiovascular development, and many result in lethality. Thus, models to study these genes in vascular remodeling processes in the adult have not been established. We have found that injured vascular cells have temporal and spatially restricted induction of the Jagged/Notch genes corresponding to periods of active cell proliferation and migration. Furthermore, using gain-of-function or loss-of-function approaches in vitro, we found that Notch controls contact inhibition of growth, migration, and cell-matrix and cell-cell contacts through cadherins/catenins. We propose to extend our studies to address the roles of Notch in vascular smooth muscle cells in vitro and in vivo during remodeling.
Our specific aims will address the following hypotheses: Notch activity regulates smooth muscle cell proliferation, survival, and migration, thus contributing to neointimal lesion development; Notch interacts with the NFKB signaling pathway and regulates cadherin/catenin function; and the inhibition of Notch activity in vivo during remodeling will decrease the amount of neointimal lesion development. To test these hypotheses, two specific aims are proposed:
Specific Aim 1 : Analyze the functions of Jagged/Notch in regulating smooth muscle cell growth and migration in vitro and restenosis in vivo using a gain-of-function or loss-of function approach.
Specific Aim 2 : Use a genetic approach to study Jagged/Notch regulation of vascular remodeling by developing transgenic models expressing Notch transgenes in an inducible, vascular-specific fashion, and by studying chimeric animals using Jagged/Notch null mutant embryonic stem cells. The goal of these studies is to understand the mechanisms by which Notch regulates smooth muscle cell behavior. In addition to the relevance of these pathways to neointimal hyperplasia and restenosis, the development of the proposed transgenic mouse models will be invaluable models to study ischemia, neovascularization, vascular development, and tumor angiogenesis.
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