Progressive intimal hyperplasia (IH) remains a major cause of intermediate and long-term failure of bypass grafts and endovascular interventions. Pharmacologic agents which inhibit this smooth muscle cell proliferative response in experimental injury models have failed to prevent occlusive IH in clinical trials suggesting that factors other than or in addition to the local response to injury may be involved. We have produced a novel and realistic rabbit model in which IH is induced to progress to an obstructive stenosis without denudation injury, by manipulation of flow. We hypothesize that local hemodynamic wall shear stress modulates the transcription of the immediate early growth response genes (c-jun and Egr-I) and their products which participate in the regulation of the cell cycle and smooth muscle cell proliferative response. Specifically, low shear stress enhances progression, and high or normal shear stress inhibits or stabilizes IH. It is further postulated that this modulation is dependent on flow mediated platelet activation. We will test these hypotheses using the rabbit iliac artery autogenous anastomosis model under conditions of: 1) normal flow, 2) low flow induced by outflow obstruction and 3) high flow induced by creation of a distal arteriovenous fistula. The time course and localization of the genetic responses to different levels of local shear stress will be determined using molecular biologic techniques. Platelet activation in the different flow settings will be assessed using thromboxane B2 analysis and inhibited by glycoprotein IIb/IIIa receptor blockade. We will correlate these findings with the local wall shear stress conditions and the magnitude and spatial distribution of subsequent IH. The flow field and wall shear stress distribution will be determined by laser Doppler anemometry and computational fluid dynamics in models which simulate the in vivo geometry and flow patterns. These studies will elucidate for the first time, the role of shear stress in modulating the early molecular events associated with induction, progression, inhibition, or stabilization of posinterventional IH.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL055296-02
Application #
2519537
Study Section
Surgery and Bioengineering Study Section (SB)
Project Start
1996-09-01
Project End
1999-08-31
Budget Start
1997-09-01
Budget End
1998-08-31
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Chicago
Department
Surgery
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
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