The mechanism by which IGF-I mediates smooth muscle cell migration and proliferation in the formation of atheromatous plaques is incompletely understood. IGF binding proteins, IGFBPs, are critical factors in this signaling cascade that control the ability of IGF-I to bind its receptor. Specifically, IGFBP-4, secreted by SMCs, inhibits the local anabolic effects of IGF-I. SMCs also secrete proteases, which degrade the IGFBP-4 thereby allowing the IGF-I to bind to its receptor. The question that is posed in this study is whether administration of a protease-resistant form of IGFBP-4 will reduce atheroma formation by blocking IGF-I binding to its receptor.
The aims of this project are to determine if infusion of a protease-resistant form of IGFBP-4 into porcine arteries will inhibit lesion formation, and whether its effect is blunted in pigs infused with the wild-type IGFBP-4. Further, it will be important to determine if the effect of IGFBP-4 is IGF-I-dependent (it can be reversed by coadministration of IGF-I) or IGF-I-independent.
The final aim will be to determine that the IGFBP-4 is intact and not degraded. By further delineating the roles of IGF-I and IGFBP- 4 in atherogenesis, these results may offer novel interventions to alter the progression of atherosclerosis.
