Vasodilator-stimulated phosphoprotein (VASP) is a focal adhesion protein, a downstream target of nitric oxide, and a substrate for cyclic GMP-dependent kinase (PKG) and cyclic AMP-dependent kinase (PKA). It promotes the elongation of actin filaments, a process required for cell motility, growth and contraction. However, its role in the function of vascular smooth muscle cells (SMCs) has not been defined; VASP-/- mice are viable and appear to have normal blood vessel structure and function. Preliminary experiments designed to define a role for VASP and VASP phosphorylation have yielded some exciting, novel results. VASP expression potentiates SMC growth while inhibiting SMC migration. VASP is phosphorylated on 3 residues (ser157, ser239, and thr278). Ser157 phosphorylation by protein kinase C (PKC) in response to serum is required for SMC growth, while ser239 phosphorylation by PKG is required for inhibition by nitric oxide and cGMP. Thus, VASP appears to be an assembly point for various kinase pathways that control SMC growth. This hypothesis will be tested in vitro and in vivo to define the mechanisms by which VASP and its phosphorylation regulates SMC proliferation and migration.
The specific aims are: 1. To examine the function of VASP in mouse SMC proliferation, migration and adhesion; 2. To determine the mechanism by which phosphorylation of ser157 and ser239 on VASP mediates VASP-induced potentiation of SMC proliferation and the inhibitory effect of NO/PKG on SMC growth, respectively; 3. To determine the role of VASP and VASP phosphorylation on the arterial response to altered flow and endothelial injury.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL052459-13
Application #
7222752
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Fleg, Jerome
Project Start
1995-05-01
Project End
2009-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
13
Fiscal Year
2007
Total Cost
$432,353
Indirect Cost
Name
University of Washington
Department
Surgery
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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