Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL052459-12
Application #
7022230
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Wassef, Momtaz K
Project Start
1995-05-01
Project End
2009-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
12
Fiscal Year
2006
Total Cost
$434,687
Indirect Cost

  Institution

Name
University of Washington
Department
Surgery
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195

  Publications

Lee, Woo Je; Tateya, Sanshiro; Cheng, Andrew M et al. (2015) M2 Macrophage Polarization Mediates Anti-inflammatory Effects of Endothelial Nitric Oxide Signaling. Diabetes 64:2836-46
Cheng, Andrew M; Rizzo-DeLeon, Norma; Wilson, Carole L et al. (2014) Vasodilator-stimulated phosphoprotein protects against vascular inflammation and insulin resistance. Am J Physiol Endocrinol Metab 307:E571-9
Braun, Kathleen R; DeWispelaere, Allison M; Bressler, Steven L et al. (2012) Inhibition of PDGF-B induction and cell growth by syndecan-1 involves the ubiquitin and SUMO-1 ligase, Topors. PLoS One 7:e43701
Handa, Priya; Tateya, Sanshiro; Rizzo, Norma O et al. (2011) Reduced vascular nitric oxide-cGMP signaling contributes to adipose tissue inflammation during high-fat feeding. Arterioscler Thromb Vasc Biol 31:2827-35
Tateya, Sanshiro; Rizzo, Norma O; Handa, Priya et al. (2011) Endothelial NO/cGMP/VASP signaling attenuates Kupffer cell activation and hepatic insulin resistance induced by high-fat feeding. Diabetes 60:2792-801
Defawe, Olivier D; Kim, Sarah; Chen, Lihua et al. (2010) VASP phosphorylation at serine239 regulates the effects of NO on smooth muscle cell invasion and contraction of collagen. J Cell Physiol 222:230-7
Grabski, Allison D; Shimizu, Takuya; Deou, Jessie et al. (2009) Sphingosine-1-phosphate receptor-2 regulates expression of smooth muscle alpha-actin after arterial injury. Arterioscler Thromb Vasc Biol 29:1644-50
Fukai, Nozomi; Kenagy, Richard D; Chen, Lihua et al. (2009) Syndecan-1: an inhibitor of arterial smooth muscle cell growth and intimal hyperplasia. Arterioscler Thromb Vasc Biol 29:1356-62
Hwang, Jin-Yong; Johnson, Pamela Y; Braun, Kathleen R et al. (2008) Retrovirally mediated overexpression of glycosaminoglycan-deficient biglycan in arterial smooth muscle cells induces tropoelastin synthesis and elastic fiber formation in vitro and in neointimae after vascular injury. Am J Pathol 173:1919-28
Huang, Robert; Merrilees, Mervyn J; Braun, Kathleen et al. (2006) Inhibition of versican synthesis by antisense alters smooth muscle cell phenotype and induces elastic fiber formation in vitro and in neointima after vessel injury. Circ Res 98:370-7

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