The investigator hypothesizes that the adventitia which is enriched in fibroblasts, plays a major role in vascular lesion formation after angioplasty and during the atherosclerosis process. Recent data indicate that the major responses immediately after angioplasty are inflammation of the adventitia and proliferation of adventitial myofibroblasts. The hypothesis is that these responses are stimulated, in part, by a reduction of adventitia blood supply by the vasa vasorum caused by balloon inflation resulting in adventitia ischemia. His work implies that one result of angioplasty may be that post angioplasty restenosis may not be caused solely by a mechanical injury of the atherosclerotic plaque and / or medial wall. Additional data from Dr. Wilcox's laboratory indicate that adventitia myofibroblasts have the potential to migrate into the neointima after angioplasty and contribute to the mass of the restenotic lesion. To address the specific aims, the applicant has designed new experiments in a well defined model of balloon overstretched injury using porcine coronary arteries. These studies will determine the extent of adventitia myofibroblast migration into the restenotic lesion, the extent of the adventitia ischemia caused by balloon inflation, and its effects on fibrosis and inflammation in the adventitia.
Four specific aims have now been designed to address the unanswered questions in this field as well as those of the previous reviewers. Firstly, the applicant will determine the contribution of adventitial myofibroblasts to the development of restenosis. Secondly, he will study the role of ischemia in stimulating adventitial inflammation and fibrosis. The applicant is particularly interested in the effect of ischemia on ICAM and IL-8 expression in the adventitia. Thirdly, the hypothesis that angioplasty causes a reduction of adventitia blood flow resulting in ischemia will be tested. Finally, the Principal Investigator will determine the role of adventitia inflammation which is associated with angioplasty in the early growth responses in the vascular wall after injury.
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