As a leading cause of restenosis, neointimal hyperplasia is common to small caliber grafting, endarterectomy and balloon angioplasty. Following surgical injury to the arterial wall, activated smooth muscle cells (SMC) migrate and then proliferate in the neointima. The accumulation of SMCs and deposition of extracellular matrix lead to a hemodynamically compromising luminal reduction, which is developed in a fraction of the time needed for the primary atherosclerotic lesion. In addition, the neointima is primarily made up of SMCs while the primary lesion is multicellular and without a dominant cell type. To prevent recurrent stenosis, this rapid accumulation of SMCs in the neointima must be inhibited; however, only minimal information is currently available on the mechanisms of accelerated SMC accumulation in the neointima. Preliminary data for this proposal indicate that migration of SMCs is critical in the development of the neointimal lesion, and the work proposed here focuses on the mechanisms of SMC migration and possible techniques to inhibit it. SMC migration is activated by chemotactic and chemokinetic signals generated following arterial injury and is mediated by interaction of SMC, integrins expressed on the cell surface and the extracellular matrix. This proposal will test the hypotheses that SMC migration can be inhibited by disrupting the actions of those mediators (e.g. growth factors, integrins and extracellular matrix) and, in turn, the neointimal lesion formation can be prevented. The mechanisms of action on the SMC by the activating signals, platelet-derived growth factor and transforming growth factor-beta, will be delineated. The role of integrin receptors (e.g. alpha-v-beta-3) and the extracellular matrix in SMC migration will be examined. To assess cell migration, in vitro and in vivo cell migration assays will be performed. To determine the effect of inhibition of SMC migration on the neointimal lesion formation, animal studies will be performed with the appropriate agonists and antagonists. The results from these studies may provide new and valuable information on the mechanism of SMC migration and inhibition of the neointimal lesion as well as insight into the development of atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL036898-06A2
Application #
2218302
Study Section
Surgery and Bioengineering Study Section (SB)
Project Start
1990-08-01
Project End
1994-09-30
Budget Start
1993-12-01
Budget End
1994-09-30
Support Year
6
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Washington University
Department
Surgery
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Choi, E T; Callow, A D; Sehgal, N L et al. (1995) Halofuginone, a specific collagen type I inhibitor, reduces anastomotic intimal hyperplasia. Arch Surg 130:257-61
Callow, A D; Choi, E T; Trachtenberg, J D et al. (1994) Vascular permeability factor accelerates endothelial regrowth following balloon angioplasty. Growth Factors 10:223-8
Choi, E T; Engel, L; Callow, A D et al. (1994) Inhibition of neointimal hyperplasia by blocking alpha V beta 3 integrin with a small peptide antagonist GpenGRGDSPCA. J Vasc Surg 19:125-34
Trachtenberg, J D; Sun, S; Choi, E T et al. (1993) Effect of endothelin-1 infusion on the development of intimal hyperplasia after balloon catheter injury. J Cardiovasc Pharmacol 22 Suppl 8:S355-9
Stevens, S L; Hilgarth, K; Ryan, U S et al. (1992) The synergistic effect of hypercholesterolemia and mechanical injury on intimal hyperplasia. Ann Vasc Surg 6:55-61
Prendiville, E J; Coleman, J E; Callow, A D et al. (1991) Increased in-vitro incubation time of endothelial cells on fibronectin-treated ePTFE increases cell retention in blood flow. Eur J Vasc Surg 5:311-9
Callow, A D (1990) The vascular endothelial cell as a vehicle for gene therapy. J Vasc Surg 11:793-8
Birinyi, L K; Warner, S J; Salomon, R N et al. (1989) Observations on human smooth muscle cell cultures from hyperplastic lesions of prosthetic bypass grafts: production of a platelet-derived growth factor-like mitogen and expression of a gene for a platelet-derived growth factor receptor--a preliminary stud J Vasc Surg 10:157-65
Connolly, R; McEnroe, C S; Li, S et al. (1988) The effect of suture material on platelet deposition onto prosthetic material. ASAIO Trans 34:874-7