Vascular smooth muscle proliferation is a key component of the process of restenosis after transluminal angioplasty. Growth factors are believed to play a critical role in modulating the response to balloon injury. Prominent amongst them is platelet-derived growth factor (PDGF), which is released from platelets upon aggregation, and also expressed by cells within the injured vascular wall. Insulin-like growth factor-I (IGF-I) markedly synergies with PDGF in promoting SMC replication. We have observed that IGF-I is expressed by medial aortic smooth muscle ells after vascular injury in-vivo. Vascular SMC not only make IGF-I, but also secrete IGF binding proteins (mainly IGFBP-4), which interact with IGF's and modulate their biological activity. a cation-dependent protease elaborated by SMC cleaves IGFBP-4, presumably releasing bioactive IGF-1. This proposal is designed to explore the regulation and biological role of the complex IGF/IGFBP system in vivo after balloon injury in rats, and in cultured vascular SMC. The relative contribution of individual growth factors or growth factor binding proteins to neointimal thickening in-vivo is hard to assess. This is particularly so for the IGF system. As IGF-I and IGFBP's are abundantly present in plasma, blocking antibodies cannot be used to interfere with the bioactivity of locally produced IGF's within the vessel wall. To better understand the paracrine role of IGF's after balloon injury, we will develop transgenic rates overexpressing either IGF-I, IGFBP-4 or mutant (uncleavable) IGFBP-4 in vascular SMC. Fertilized rat eggs will be microinjected with a fusion gene containing the regulatory sequences of the smooth muscle cell alpha actin gene coupled to full length rat IGF-I and/or IGFBP-4 cDNA. The impact of expression of these transgenes on neointimal thickening will then be determined. Ultimately, this transgenic model will be useful tool to study the impact of other proteins in the IGF pathway, as well as other growth factors and growth factor antagonists, in the arterial response to injury.
