The goal of this proposal is to further our understanding of the basic pathogenic mechanisms that occur in the vessel wall of veins transplanted to the arterial circulation at the tissue, cellular and molecular level. Transplantation of vein to the arterial circulation inevitably results in desquamation of the venous endothelium followed by smooth muscle cell proliferation with the formation of intimal hyperplasia. Of the grafts that fail 25% do so because of these adverse changes within the graft wall itself. It is the specific aim of this proposal to define the role of platelets and inflammatory cells in the initiation of vein graft intimal hyperplasia; to determine the underlying reasons for the susceptibility of intimal hyperplasia to atherosclerosis; to examine the mechanisms of self-limitation of intimal thickening; and to determine the vasofunction of intimal hyperplastic vasculature. To accomplish this we propose a comprehensive approach using large and small animal models and tissue culture systems. A detailed morphological examination of vein graft intimal hyperplasia is proposed with particular reference to the time course and role of inflammatory cells in its development. We propose to examine the susceptibility of these grafts to the development of atherosclerosis and to look at specific pharmacological interventions to prevent the development of intimal hyperplasia in vein grafts. Experiments to assess the in vivo relevance of the supersensitivity of intimal hyperplastic vasculature to catecholamines are described and these studies will be extended to an examination of the reactivity of vein grafts with developing intimal hyperplasia and the possible additional effect of hypercholesterolemia in vascular reactivity. We will examine the possibility of common cellular pathways for mitogen and catecholamine stimulation and the functional importance of these pathways in cellular proliferation. On the molecular level, we propose to assess the role of mitogens on the stimulation of vascular cells in culture, particularly the role of the neutrophil derived growth factor. We propose to examine the role of substances such as heparin-like molecules on the inhibition of vascular cell proliferation and eicosanoids in regulating vascular cell proliferation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL015448-17
Application #
3334955
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1976-05-01
Project End
1991-03-31
Budget Start
1990-04-01
Budget End
1991-03-31
Support Year
17
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Duke University
Department
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Zhang, Lisheng; Hagen, Per-Otto; Kisslo, Joseph et al. (2002) Neointimal hyperplasia rapidly reaches steady state in a novel murine vein graft model. J Vasc Surg 36:824-32
Huynh, T T; Davies, M G; Thompson, M A et al. (2001) Local treatment with recombinant tissue factor pathway inhibitor reduces the development of intimal hyperplasia in experimental vein grafts. J Vasc Surg 33:400-7
Davies, M G; Huynh, T T; Hagen, P O (2000) Characterization of dopamine-mediated relaxation in experimental vein bypass grafts. J Surg Res 92:103-7
Davies, M G; Fulton, G J; Huynh, T T et al. (1999) Combination therapy of cholesterol reduction and L-arginine supplementation controls accelerated vein graft atheroma. Ann Vasc Surg 13:484-93
Huynh, T T; Davies, M G; Trovato, M J et al. (1999) Alterations in wall tension and shear stress modulate tyrosine kinase signaling and wall remodeling in experimental vein grafts. J Vasc Surg 29:334-44
Davies, M G; Huynh, T T; Hagen, P O (1999) Functional characterization of alpha1-adrenergic receptors in experimental vein grafts. J Surg Res 84:40-5
Davies, M G; Hagen, P O (1999) Diabetes attenuates the alterations in both venous endothelial and smooth muscle cell function induced by prolonged hypercholesterolemia in an experimental model. J Invest Surg 12:107-14
Davies, M G; Fulton, G J; Svendsen, E et al. (1999) Time course of the regression of intimal hyperplasia in experimental vein grafts. Cardiovasc Pathol 8:161-8
Davies, M G; Huynh, T T; Fulton, G J et al. (1999) Early morphology of accelerated vein graft atheroma in experimental vein grafts. Ann Vasc Surg 13:378-85
Davies, M G; Huynh, T T; Fulton, G J et al. (1999) Controlling transplant vasculopathy in cryopreserved vein grafts with polyethylene glycol and glutathione during transport. Eur J Vasc Endovasc Surg 17:493-500

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