More than 3 million procedures (eg angioplasty) are performed each year to open blocked arteries. Unfortunately, one in three will fail in the short term from recurrent blockage at the site of repair, termed restenosis. Restenosis has traditionally been attributed to the accumulation of smooth muscle cells and their extracellular matrix at sites of injury. More recently, shrinkage of the artery wall as it heals (inward or constrictive remodeling) has been found to contribute more to lumen narrowing after angioplasty than new wall mass per se. The cellular and molecular basis of remodeling is poorly defined. This the broad objectives of the research program are to define mechanisms driving constrictive remodeling after angioplasty. HA is a large glycoaminoglycan prominent in matrix deposited at sites of angioplasty and remodeling. HA is known to enhance collagen reorganization by fibroblasts in wounds and to speed wound closure, prompting the focus of the research on collagen-HA interactions in the injured artery wall. HA receptors are important for arterial smooth muscle cell growth and migration in vitro. Contraction of collagen is enhanced in the presence of HA and limited by blocking HA receptors. Fragments of HA have been developed to block HA-receptors and inhibit intimal hyperplasia in rats and rabbits. Collagen and HA are prominent components of the healing response after angioplasty in atherosclerotic arteries and the PI's studies suggest that the mechanism of wall shrinkage is collagen reorganization by smooth muscle cells and adventitial fibroblasts. This proposal aims to employ HA-receptor knockout mice to study the role of these receptors in smooth muscle cells contraction of collagen gels in vitro and the impact of HA-receptor deletions on carotid artery constrictive remodeling in vivo. A unique model of angioplasty in atherosclerotic monkeys will also be used to test the hypothesis that a non selective HA receptor antagonist infused for 4 weeks will inhibit artery wall constriction and restenosis. Separate studies will explore the gene expression patterns induced during constrictive remodeling by applying RNA from arteries after injury, and from smooth muscle cells contracting collagen in vitro, to human gene arrays.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL057557-06
Application #
6724944
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
Sopko, George
Project Start
1998-05-01
Project End
2007-02-28
Budget Start
2004-03-01
Budget End
2005-02-28
Support Year
6
Fiscal Year
2004
Total Cost
$324,000
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Surgery
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Ma, Xue; Pearce, Jeffrey D; Wilson, David B et al. (2014) Loss of the hyaluronan receptor RHAMM prevents constrictive artery wall remodeling. J Vasc Surg 59:804-13
Corriere, Matthew A; Edwards, Matthew S; Pearce, Jeffrey D et al. (2009) Restenosis after renal artery angioplasty and stenting: incidence and risk factors. J Vasc Surg 50:813-819.e1
Vaisar, Tomas; Pennathur, Subramaniam; Green, Pattie S et al. (2007) Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL. J Clin Invest 117:746-56
Adams, Lawrence D; Geary, Randolph L; Li, Jing et al. (2006) Expression profiling identifies smooth muscle cell diversity within human intima and plaque fibrous cap: loss of RGS5 distinguishes the cap. Arterioscler Thromb Vasc Biol 26:319-25
Pearce, Jeffrey D; Li, Jing; Edwards, Matthew S et al. (2004) Differential effects of Rho-kinase inhibition on artery wall mass and remodeling. J Vasc Surg 39:223-8
Li, Jing; Adams, Lawrence D; Wang, Xi et al. (2004) Regulator of G protein signaling 5 marks peripheral arterial smooth muscle cells and is downregulated in atherosclerotic plaque. J Vasc Surg 40:519-28
Geary, Randolph L; Wong, James M; Rossini, Anthony et al. (2002) Expression profiling identifies 147 genes contributing to a unique primate neointimal smooth muscle cell phenotype. Arterioscler Thromb Vasc Biol 22:2010-6
Cherr, Gregory S; Motew, Stephen J; Travis, Jeffrey A et al. (2002) Metalloproteinase inhibition and the response to angioplasty and stenting in atherosclerotic primates. Arterioscler Thromb Vasc Biol 22:161-6
Travis, J A; Hughes, M G; Wong, J M et al. (2001) Hyaluronan enhances contraction of collagen by smooth muscle cells and adventitial fibroblasts: Role of CD44 and implications for constrictive remodeling. Circ Res 88:77-83
Fukuhara, M; Geary, R L; Diz, D I et al. (2000) Angiotensin-converting enzyme expression in human carotid artery atherosclerosis. Hypertension 35:353-9

Showing the most recent 10 out of 12 publications