In spite of the local production of cytotoxic agents within a proinflammatory environment, normally quiescent endothelial cells proliferate, migrate, and form new vascular structures. Consequently, mechanisms regulating angiogenesis remain a fundamental issue in vascular biology. The maintenance of endothelial integrity includes the responsibility of acidic fibroblast growth factor (FGF-1). Ongoing studies in this laboratory have identified a nonconventional pathway for cellular secretion of FGF-1 that is induced by oxidative stress associated with inflammation and mediated by reactive nitrogen species (RNS). As an extracellular protein, FGF-1 can either enhance or inhibit endothelial cell death induced by RNS. This paradoxical FGF-1 effect appears dependent upon different signal transduction cascades induced by alternatively spliced FGF receptor-1 (FGFR-1) structural isoforms. These observations imply a pivotal role for FGF-1/FGFR-1 during the resolution of inflammation and repair. Experimental aims are designed within the framework of the hypothesis that within a proinflammatory environment, pro-oxidant agents induce cellular release of FGF-1, which as an extracellular protein activates isoform-specific FGFR-1-mediated signal transduction cascades that differentially modulate cellular growth and death responses. An underlying theme includes quantitating production and targeted molecular responses to pro-oxidant RNS that modulate antioxidant defense mechanisms. The availability of established cells, reagents, interventional agents, and techniques permit fundamental mechanistic studies in vitro. The opportunity to dissect and modulate FGF-1 secretion and FGFR-1 signaling in endothelial cells is complemented by the ability to extend this molecular paradigm into relevant rodent models of cell/kidney transplantation. Elucidation of the molecular events responding to proinflammatory RNS, FGF-1 secretion, and FGFR-1 signaling will reveal detailed characteristics of these interrelationships, provide diagnostic criteria for monitoring this process, and establish more rational interventional strategies associated with angiogenesis.
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