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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL070865-04
Application #
7091707
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Program Officer
Tolunay, Eser
Project Start
2003-07-01
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2008-06-30
Support Year
4
Fiscal Year
2006
Total Cost
$372,535
Indirect Cost
Name
Maine Medical Center
Department
Type
DUNS #
071732663
City
Portland
State
ME
Country
United States
Zip Code
04102
Davis-Knowlton, Jessica; Turner, Jacqueline E; Turner, Anna et al. (2018) Characterization of smooth muscle cells from human atherosclerotic lesions and their responses to Notch signaling. Lab Invest :
Peterson, Sarah M; Turner, Jacqueline E; Harrington, Anne et al. (2018) Notch2 and Proteomic Signatures in Mouse Neointimal Lesion Formation. Arterioscler Thromb Vasc Biol 38:1576-1593
Liaw, Lucy; Prudovsky, Igor; Koza, Robert A et al. (2016) Lipid Profiling of In Vitro Cell Models of Adipogenic Differentiation: Relationships With Mouse Adipose Tissues. J Cell Biochem 117:2182-93
Bishop, Kathleen A; Harrington, Anne; Kouranova, Evguenia et al. (2016) CRISPR/Cas9-Mediated Insertion of loxP Sites in the Mouse Dock7 Gene Provides an Effective Alternative to Use of Targeted Embryonic Stem Cells. G3 (Bethesda) 6:2051-61
Rostama, Bahman; Turner, Jacqueline E; Seavey, Guy T et al. (2015) DLL4/Notch1 and BMP9 Interdependent Signaling Induces Human Endothelial Cell Quiescence via P27KIP1 and Thrombospondin-1. Arterioscler Thromb Vasc Biol 35:2626-37
Young, Kira; Tweedie, Eric; Conley, Barbara et al. (2015) BMP9 Crosstalk with the Hippo Pathway Regulates Endothelial Cell Matricellular and Chemokine Responses. PLoS One 10:e0122892
Rostama, Bahman; Peterson, Sarah M; Vary, Calvin P H et al. (2014) Notch signal integration in the vasculature during remodeling. Vascul Pharmacol 63:97-104
Boucher, Joshua M; Harrington, Anne; Rostama, Bahman et al. (2013) A receptor-specific function for Notch2 in mediating vascular smooth muscle cell growth arrest through cyclin-dependent kinase inhibitor 1B. Circ Res 113:975-85
Yang, Xuehui; Gong, Yan; Tang, Yuefeng et al. (2013) Spry1 and Spry4 differentially regulate human aortic smooth muscle cell phenotype via Akt/FoxO/myocardin signaling. PLoS One 8:e58746
Tang, Yuefeng; Bai, Hao; Urs, Sumithra et al. (2013) Notch1 activation in embryonic VE-cadherin populations selectively blocks hematopoietic stem cell generation and fetal liver hematopoiesis. Transgenic Res 22:403-10

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