Approximately 30% of vascular interventions using grafts and stents to correct the problems associated with atherosclerosis fail largely as a result of intimal hyperplasia resulting from smooth muscle cell (SMC) growth and wall thickening. While most research has been directed at preventing wall thickening, an alternative might be to stimulate neointimal atrophy after lumenal narrowing has developed. We have demonstrated that high blood flow induces neointimal atrophy in baboon PTFE grafts, but not in the normal iliac artery. We have also found that bone morphogenetic protein (BMP}-4 is induced by high blood flow, while the. BMP inhibitor noggin is suppressed. We propose to test the hypothesis that neointimal atrophy requires a loss of wall tension in the presence of inflammation by comparing loose and tight PTFE wraps around the baboon artery with high blood flow. We will use subtractive suppressive hybridization with DMA microarrays to identify a short list of genes that are regulated during atrophy of both graft neointima and artery and will then determine whether these genes are expressed (or repressed) in the thinning fibrous cap of stenotic atherosclerotic human carotid arteries. We will determine whether baboon neointimal atrophy involves the loss of specific matrix molecules (especially versican) by quantitating glycosaminoglycans using fluorophore assisted carbohydrate electrophoresis. Finally, we will test the hypothesis that an established neointima can be induced pharmacologically to atrophy by overexpressing BMP-4 in the face of normal blood flow. In addition, we will test whether overexpressing noggin blocks high blood flow-mediated neointimal atrophy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL030946-25
Application #
7477188
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Lundberg, Martha
Project Start
1983-07-01
Project End
2010-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
25
Fiscal Year
2008
Total Cost
$547,800
Indirect Cost
Name
University of Washington
Department
Surgery
Type
Schools of Medicine
DUNS #
605799469
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
Kikuchi, Shinsuke; Chen, Lihua; Xiong, Kevin et al. (2018) Smooth muscle cells of human veins show an increased response to injury at valve sites. J Vasc Surg 67:1556-1570.e9
Kenagy, Richard D; Kikuchi, Shinsuke; Evanko, Steve P et al. (2018) Versican is differentially regulated in the adventitial and medial layers of human vein grafts. PLoS One 13:e0204045
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Kikuchi, Shinsuke; Kenagy, Richard D; Gao, Lu et al. (2016) Surgical marking pen dye inhibits saphenous vein cell proliferation and migration in saphenous vein graft tissue. J Vasc Surg 63:1044-50
Kenagy, Richard D; Civelek, Mete; Kikuchi, Shinsuke et al. (2016) Scavenger receptor class A member 5 (SCARA5) and suprabasin (SBSN) are hub genes of coexpression network modules associated with peripheral vein graft patency. J Vasc Surg 64:202-209.e6
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
Braun, Kathleen R; DeWispelaere, Allison M; Bressler, Steven L et al. (2012) Inhibition of PDGF-B induction and cell growth by syndecan-1 involves the ubiquitin and SUMO-1 ligase, Topors. PLoS One 7:e43701

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