Neointimal fibroproliferation is the pathological process that underlies restenosis after angioplasty. The pathophysiological events resulting in neointimal proliferation can be divided into three stages: the acute initiating phase in response to injury, the intermediate phase of smooth muscle migration and proliferation, and the chronic perpetuating phase of neointimal proliferation. The purpose of this research will be to elucidate basic mechanisms involved in the initiating phase of neointimal fibroproliferation following mechanically-induced endothelial injury resulting from coronary artery angioplasty in canine models with and without intrinsic coronary atherosclerosis. Based on mechanistic insights gained, we hope to develop protective therapies that prevent neointimal fibroproliferation following balloon angioplasty. Cell culture tissues and chronically instrumented canine models with and without native coronary artery atherosclerosis will be used to rest the following hypotheses: (a) Platelet aggregation, platelet-vessel wall interaction and the release f platelet-derived products are necessary for the development of neointimal fibroproliferation; (b) Platelet-derived vasoactive substances (thromboxane A2 and serotonin) and vessel wall- derived vasoactive substances (angiotensin II) interact synergistically with other locally generated growth factors to initiate the process of neointimal fibroproliferation and restenosis that occurs after coronary artery angioplasty; (c) Fibroblast growth factor and its receptors play a role in the neointimal proliferation that occurs following balloon angioplasty, and they are increased following endothelial injury from coronary artery angioplasty in dogs with and without coronary artery atherosclerosis; and (d) An inhibitor of smooth muscle cell proliferation, saporin, linked to fibroblast growth factor or to specific monoclonal antibodies directed at fibroblast growth factor receptors, in conjunction with inhibitors of platelet aggregation (e.g. antagonists of thromboxane A2 and serotonin) markedly attenuates neointimal proliferation following endothelial injury induced by angioplasty.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL050179-01
Application #
3369181
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
1993-06-01
Project End
1997-05-31
Budget Start
1993-06-01
Budget End
1994-05-31
Support Year
1
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Type
Schools of Medicine
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77225
Shelat, H S; Liu, T J; Hickman-Bick, D L et al. (2001) Growth suppression of human coronary vascular smooth muscle cells by gene transfer of the transcription factor E2F-1. Circulation 103:407-14
Zoldhelyi, P; Chen, Z Q; Shelat, H S et al. (2001) Local gene transfer of tissue factor pathway inhibitor regulates intimal hyperplasia in atherosclerotic arteries. Proc Natl Acad Sci U S A 98:4078-83
Jax, T W; Eichstaedt, H C; Shelat, H S et al. (2000) [New antithrombotic therapy approaches in coronary heart disease--prospects for gene therapy] Z Kardiol 89:1072-83
Zoldhelyi, P; Beck, P J; Bjercke, R J et al. (2000) Inhibition of coronary thrombosis and local inflammation by a noncarbohydrate selectin inhibitor. Am J Physiol Heart Circ Physiol 279:H3065-75
Zoldhelyi, P; Eichstaedt, H; Jax, T et al. (1999) The emerging clinical potential of cardiovascular gene therapy. Semin Interv Cardiol 4:151-65
Patel, S S; Thiagarajan, R; Willerson, J T et al. (1998) Inhibition of alpha4 integrin and ICAM-1 markedly attenuate macrophage homing to atherosclerotic plaques in ApoE-deficient mice. Circulation 97:75-81
Pakala, R; Willerson, J T; Benedict, C R (1997) Effect of serotonin, thromboxane A2, and specific receptor antagonists on vascular smooth muscle cell proliferation. Circulation 96:2280-6
Willerson, J T; Igo, S R; Yao, S K et al. (1996) Localized administration of sodium nitroprusside enhances its protection against platelet aggregation in stenosed and injured coronary arteries. Tex Heart Inst J 23:1-8
Willerson, J T; Zoldhelyi, P; Meidell, R et al. (1995) Gene therapy to restore prostacyclin presence to injured endothelium. Trans Am Clin Climatol Assoc 106:100-7;discussion 107-8
Yao, S K; Akhtar, S; Scott-Burden, T et al. (1995) Endogenous and exogenous nitric oxide protect against intracoronary thrombosis and reocclusion after thrombolysis. Circulation 92:1005-10

Showing the most recent 10 out of 14 publications