In vivo, mechanical denuding arterial injury initiates platelet-rich thrombus formation and subsequently gives rise to proliferative intimal vascular lesion formation (VLF), both experimentally in normal arteries and clinically in atherosclerotic vessels undergoing interventional procedures for symptomatic disease. We postulate that the complex processes leading to vascular lesion formation at sites of mechanical vascular damage include: a) loss of antithrombotic and antiproliferative endothelial cell (EC) functions; b) generation of thrombin mitogenic activity in forming and healing thrombus; c) deposition of platelet- derived growth factor (PDGF) mitogenic activity released from activated platelets accumulating during acute thrombus formation; and d) local synthesis by vascular wall cells of growth factors regulated in part by thrombin, and of proteins modifying thrombin generation. We propose to test these hypotheses using specific interventions in well-characterized clinically-relevant nonhuman primate models of VLF. To simulate the complexities of human restenotic lesions, these VLF models include measured responses to both: a) simple mechanical injury of normal arteries produced by balloon catheter angioplasty (BCA), surgical endarterectomy (EA), and implanted prosthetic vascular grafts (PVG); and b) BCA injury added to already established VLF previously induced by prior BCA, EA and PVG. Initial studies will establish a time-course for cell proliferation, thrombus formation, thrombin generation and growth factor gene expression by in situ hybridization and immunohistochemistry after single and double injuries of baboon arteries. Subsequent experiments will specifically test the hypotheses by a) acutely establishing confluent endothelial cell lining of the injured surface by sodding with autologous endothelial cells; b) inhibiting thrombin action during the period of VLF using a non-toxic irreversible antithrombin (D-Phe-Pro-Arg chlormethyl ketone) by continuous intravenous infusion; c) inhibiting platelet adhesion to the injured vessel surface by producing profound thrombocytopenia using a monoclonal antibody directed against platelet glycoprotein Ib, or reducing platelet cohesion by continuous intravenous infusions of a specific platelet glycoprotein IIb/IIIa synthetic cyclic peptide antagonist.
NIH ExPorter
NIH ExPorter