Vein responds structurally, or remodel, after being transplanted into the arterial circulation, a process referred to as arterialization. A study of this phenomenon has the potential to yield major scientific insights into the effects of blood pressure and flow on vascular structure. In addition, the process of venous arterialization has major clinical significance, as saphenous veins are used to perform arterial bypass grafting in patients with advanced coronary artery and peripheral artery disease. A major limitation of surgical revascularization is the development of excessive intimal hyperplasia within bypass grafts, which can obstruct blood flow and produce tissue ischemia. Plasminogen activator inhibitor-1 (PAI-1) is a serine protease inhibitor and a major regulator of fibrinolysis and cell migration. PAI-1 function is highly dependent on its cofactor, vitronectin (VN). Our laboratory has developed a murine model of bypass grafting that involves transplantation of a segment of the inferior vena cava into the carotid artery. We have shown that PAI-1-deficient mice develop increased intimal hyperplasia within vein grafts. We hypothesize that PAI-1 is a major regulator of vein graft arterialization via its effects on plasmi-activated vascular remodeling proteases, cell migration, and the structural properties of the extracellular matrix of the vein graft wall. We also hypothesize that PAI-1 is a downstream mediator of the adverse effects of reduced blood flow on vein graft remodeling. We propose the following specific aims to test our hypotheses: 1. Determine the effects of genetic deficiency and transgenic over-expression of PAI-1 on the activities of matrix metalloproteinase-2 (MMP-2), MMP-9, neutrophil elastase, and thrombin within vein grafts. Based on results, use a double-knock-out strategy involving MMP-2-, MMP-9-, or neutrophil-elastase-deficient mice to determine the roles of these downstream proteases in mediating PAI-1's effects on vein graft remodeling. 2. Use recombinant PAI-1 proteins to probe the roles of PAI-1's anti-protease, VN-binding, and LDL receptor-related protein (LRP)-binding domains in vein graft remodeling. 3. Study the effects of reduced blood flow on the expression of PAI-1 and VN in vein grafts and examine the role of PAI-1 as a downstream mediator of blood flow's effects on vein graft remodeling. 4. Determine the impact of genetic alterations in expression levels of PAI-1 and VN on the composition and structure of the extracellular matrix of vein grafts. We will work with a experienced team of collaborators and employ cutting-edge imaging and structure-function approaches to achieve our scientific objectives. We anticipate that the proposed experiments will yield important insights into the molecular and cellular mechanisms that regulate the structural remodeling of veins after bypass surgery. In particular, the proposed studies will increase our understanding of how the fibrinolytic system intersects with other protease networks to regulate vein graft remodeling and yield novel data regarding the structural changes that occur in the extracellular matrix of the vein graft wall during arterialization. We anticipate that the information gained from our experiments will lead to new strategies to treat and prevent vein graft disease.
Each year many thousands of veterans undergo coronary artery and peripheral artery bypass graft surgery to treat blocked coronary and peripheral arteries. Veins harvested from the legs are commonly used as bypass grafts. However, within 10 years after bypass surgery 40% of all cardiac venous bypass grafts occlude and the majority of peripheral arterial venous bypass grafts occlude, often with life-threatening consequences. The molecular and cellular processes that cause vein bypass grafts to remodel, narrow, and occlude are not well understood. The proposed experiments will examine the roles of plasminogen activator inhibitor-1 (PAI-1) and vitronectin (VN), proteins that control blood clotting and cell migration, in the remodeling of bypass grafts. We anticipate that the information gained from our studies will lead to new approaches to prevent and treat vein bypass graft disease.
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