Mechanical Stretch and Vein Graft Intimal Hyperplasia

Michigan Technological University, Houghton MI

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Abstract

DESCRIPTION (provided by applicant): Vein bypass grafts are commonly used to replace malfunctioned arteries. However, vein grafts fail due to intimal hyperplasia induced by mechanical stretch and vortex blood flow. Mechanical stretch has been shown to induce extensive vascular cell death followed shortly thereafter by excessive vascular cell proliferation and intimal hyperplasia. Our long term goal is to determine a relationship of early stage mechanical stretch dependent vascular cell death to late stage vascular cell proliferation and intimal hyperplasia in a vein graft. Elucidation of a relationship between vascular cell death and proliferation may provide novel methods to prevent or reduce intimal hyperplasia, which is a critical event in the failure of veil grafts. Because vortex blood flow contributes to vein graft injury and remodeling and can obscure the role of mechanical stretch, we have developed an entirely novel experimental vein graft model where the development of vortex blood flow is prevented by closely matching graft and host artery diameters. Therefore, our model uniquely allows us to investigate the role of mechanical stretch in a physiologically relevant model without the confounding influence of vortex blood flow. We plan to approach our goal in the following stages: 1) clarify the signaling molecules that mediate stretch dependent vascular cell death during early stages of experimental vein graft remodeling; 2) clarify the signaling molecules and growth factors that mediate stretch-dependent vascular cell proliferation and intimal hyperplasia; 3) determine whether the degree of vascular cell death influences the production of growth factors and the degree of subsequent vascular cell proliferation and intimal hyperplasia. Specific Aim I: Investigate the role of p38 MAPK and JNK-SAPK in mediating stretch-dependent cell death in experimental vein grafts. Specific Aim II: Investigate the role of platelet-derived growth factor (PDGF)-BB and related signaling molecules in mediating subsequent vascular cell proliferation.