Syndecans (syndecans-1, -2, -3, and -4) are transmembrane heparan and chondroitin sulfate proteoglycans (HSPGs), which are expressed by arterial smooth muscle cells (SMCs), are regulated in injured arteries, bind various growth factors and components of the extracellular matrix (ECM), and are important regulators of cell-growth factor, cell-cell, and cell-ECM interactions. While it is known that heparan sulfate glycosaminoglycans and heparin suppress injury-induced intimal thickening by inhibiting SMC migration and proliferation and by altering SMC ECM production, the role of syndecans in SMC growth and the response to arterial injury has not been defined. We have recently found that intimal thickening and medial proliferation are markedly increased in the injured carotid arteries of syndecan-1 null mice. In addition, cultured arterial SMCs from these mice express higher levels of PDGF-B mRNA and migrate and proliferate more than SMCs from wild-type mice in response to PDGF-BB, serum, EGF, FGF2, and thrombin. siRNAs for PDGF-B chain and PDGFR-beta knock down their respective targets and suppress thrombin-, PDGF-BB-, and serum-induced SMC proliferation. These findings demonstrate to us that syndecan-1 is a negative regulator of arterial SMC growth. The major goal of this proposal is to determine how syndecan-1 transcription is regulated and how syndecan-1 then controls PDGF-B induction in response to growth factors.
The specific aims are: 1. To define the mechanism of syndecan-1 regulation in vitro and in vivo;2. To define the mechanisms by which syndecan-1 inhibits thrombin-mediated induction of PDGF-B chain;and 3. To determine in structure-function studies whether the syndecan-1 ectodomain, the cytoplasmic domain, or both are required for syndecan-1 inhibition of PDGF-B induction and cell growth. The proposed studies should provide novel insights regarding syndecan-1, which will then form the basis for the development of pharmacology to prevent restenosis, a problem that affects large numbers of patients undergoing coronary stent angioplasty.

Public Health Relevance

The proposed studies should provide novel insights regarding syndecan-1, a molecule expressed by smooth muscle cells that suppresses the formation of intimal thickening after arterial injury. These observations will then form the basis for the development of pharmacology to prevent restenosis, a problem that affects large numbers of patients undergoing coronary stent angioplasty.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL092928-03
Application #
8286917
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Olive, Michelle
Project Start
2010-08-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$412,925
Indirect Cost
$155,293
Name
University of Washington
Department
Surgery
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195