Vascular reconstructions with synthetic prostheses fail because of their thrombogenic surfaces and, at late times, because of excessive neointimal thickening. The overall objectives of this proposal are to define conditions optimal for the spontaneous formation of a non-thrombogenic endothelialized surface and to define what factors regulate subsequent neointimal smooth muscle cell (SMC) growth in a baboon model of synthetic arterial graft failure. Our recent studies on the healing of polytetrafluorethylene (PTFE) grafts suggest that an endothelialized surface can be induced by altering graft porosity and allowing transmural capillary ingrowth. We have also shown that late neointimal thickening is the consequence of SMC proliferation underneath an intact endothelium. We now plan to investigate the role of graft porosity, structure, and length in the development of the endothelial layer and subsequent intimal thickening. We will attempt to limit SMC growth in the intima with heparin (a direct inhibitor of SMC growth). Finally, we will explore the hypothesis that vascular wall cells (endothelium and SMC) themselves regulate SMC growth in the graft intima by the production of growth factor. These studies have potential clinical application since heparin-like drugs may prove useful in preventing the failure of vascular reconstructions caused by exuberant myointimal thickening. Furthermore, such studies may shed light on the in vivo mechanisms of smooth muscle growth control in healing vascular grafts. Light and electron microscopy, cell culture, thymidine autoradiography, Northern blot analysis, and in situ hybridization will be used in these experiments.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL030946-05
Application #
3341963
Study Section
Surgery and Bioengineering Study Section (SB)
Project Start
1983-07-01
Project End
1992-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
5
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Sobel, Michael; Kikuchi, Shinsuke; Chen, Lihua et al. (2018) Clinical factors that influence the cellular responses of saphenous veins used for arterial bypass. J Vasc Surg 68:165S-176S.e6
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Siew, Edward D; Himmelfarb, Jonathan (2013) The inexorable rise of AKI: can we bend the growth curve? J Am Soc Nephrol 24:3-5
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Conte, Michael S; Owens, Christopher D; Belkin, Michael et al. (2013) A single nucleotide polymorphism in the p27(Kip1) gene is associated with primary patency of lower extremity vein bypass grafts. J Vasc Surg 57:1179-85.e1-2
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