Smooth muscle cell phenotype transition, migration and survival are required for neointimal formation and vascular remodeling. These events are thought to be prerequisites for luminal narrowing in atherosclerotic and restenotic diseases. We hypothesize that cell/extracellular matrix interactions regulate smooth muscle cell phenotype, movement, and survival in response to injury. To test this hypothesis, this proposal focuses on the adhesive proteins, osteopontin and alphavbeta3 integrin. In the first aim, we will test the hypothesis that osteopontin promotes vascular repair in response to injury and increases atherosclerotic lesion formation. We will use genetically defined mouse mutants to investigate the function of osteopontin in vascular repair and atherosclerotic disease. In the second part, we will test the hypothesis that osteopontin is a survival factor for vascular smooth muscle cells. The mechanism by which osteopontin protects against fas-induced death will be delineated in vitro. In the third part, we will test the hypothesis that adhesive protein gene expression in smooth muscle cells in regulated both by the phenotypic state of the cells, and by the nature of the surrounding extracellular matrix. We will define promoter regions which control phenotype-dependent expression of osteopontin in vitro and in vivo, and delineate the mechanism whereby osteopontin, but not fibronectin or laminin induced osteopontin gene expression in vascular smooth muscle cells in vitro. Finally, we will test the hypothesis that the alphavbeta3 is required for smooth muscle cell migration following arterial injury in the rat. These experiments will identify key adhesive proteins and ECM/cell interactions required for vascular smooth muscle responses to injury. These molecules and processes may be useful targets for therapies aimed at controlling atherosclerotic and restenotic disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL003174-45
Application #
6302087
Study Section
Project Start
2000-03-01
Project End
2001-02-28
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
45
Fiscal Year
2000
Total Cost
$177,104
Indirect Cost
Name
University of Washington
Department
Type
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
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