Abstract

Modification of heparan sulfate (HS) expression on cell surfaces and the extracellular matrix (ECM) provides an important pathway for regulation of growth, differentiation, and development of numerous cell types including vascular endothelial and smooth muscle cells. Recent developments in the field suggest, however, that HS-carrying core proteins themselves are directly involved in outside-in signal transduction. In this grant application, we propose to explore these issues in the context of angiogenesis. The proposal is based on our recent demonstration of a complex series of events involved in modulation of syndecan-4 phosphorylation, which in turn plays a crucial role in the regulation of syndecan-4-dependent activation of PKC-alpha. In addition, we have isolated and identified 2 new proteins for this project that is focused on elucidation of the molecular events involved in syndecan-4- mediated signaling in endothelial cells.
The specific aims of this study include: 1) Regulation of syndecan-4 phosphorylation 2) Syndecan- dependent regulation of PKC-a activity; 3) In vivo studies of syndecan-r dependent signal transduction.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL063609-02
Application #
6445196
Study Section
Special Emphasis Panel (ZHL1)
Project Start
2001-04-01
Project End
2001-04-02
Budget Start
Budget End
Support Year
2
Fiscal Year
2001
Total Cost
$219,340
Indirect Cost

  Institution

Name
Harvard University
Department
Type
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115

  Publications

Wykrzykowska, Joanna J; Rosinberg, Audrey; Lee, Seung U et al. (2011) Autologous cardiomyotissue implantation promotes myocardial regeneration, decreases infarct size, and improves left ventricular function. Circulation 123:62-9
Wu, Guifu; Rana, Jamal S; Wykrzykowska, Joanna et al. (2009) Exercise-induced expression of VEGF and salvation of myocardium in the early stage of myocardial infarction. Am J Physiol Heart Circ Physiol 296:H389-95
Wu, Gui Fu; Wykrzykowska, Joanna J; Rana, Jamal S et al. (2008) Effects of B-type natriuretic peptide (nesiritide) on coronary epicardial arteries, systemic vasculature and microvessels. J Invasive Cardiol 20:76-80
Voisine, Pierre; Rosinberg, Audrey; Wykrzykowska, Joanna J et al. (2008) Skin-derived microorgan autotransplantation as a novel approach for therapeutic angiogenesis. Am J Physiol Heart Circ Physiol 294:H213-9
Post, Mark J; Sato, Kaori; Murakami, Masahiro et al. (2006) Adenoviral PR39 improves blood flow and myocardial function in a pig model of chronic myocardial ischemia by enhancing collateral formation. Am J Physiol Regul Integr Comp Physiol 290:R494-500
Tkachenko, Eugene; Rhodes, John M; Simons, Michael (2005) Syndecans: new kids on the signaling block. Circ Res 96:488-500
Abid, Md Ruhul; Yano, Kiichiro; Guo, Shaodong et al. (2005) Forkhead transcription factors inhibit vascular smooth muscle cell proliferation and neointimal hyperplasia. J Biol Chem 280:29864-73
Friehs, Ingeborg; Cao-Danh, Hung; Nathan, Meena et al. (2005) Impaired insulin-signaling in hypertrophied hearts contributes to ischemic injury. Biochem Biophys Res Commun 331:15-22
Tkachenko, Eugene; Lutgens, Esther; Stan, Radu-Virgil et al. (2004) Fibroblast growth factor 2 endocytosis in endothelial cells proceed via syndecan-4-dependent activation of Rac1 and a Cdc42-dependent macropinocytic pathway. J Cell Sci 117:3189-99
Aird, William C (2004) Natural anticoagulant inhibitors: activated Protein C. Best Pract Res Clin Haematol 17:161-82

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