Raf 1-ERK cross-talk in Arteriogenesis

Yale University, New Haven CT

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Abstract

PROJECT SUMMARY (See instructions): Arteriogenesis is the process of formation of new arterial blood vessels during development or in the adult circulation. In development it entails formation of new endothelial vascular structures with arterial identity as defined by expression of key markers such ephrin B2 and neuropilin 1 followed by acquisition of the media and adventitia. In the adult circulation new arteries arise either by expansion of the pre-existing arterial vascular structures or de novo. Deletion of VEGF, its receptor VEGFR2 or key intracellular signaling mediators results in failure of arterial vasculature development. Defective arteriogenesis is noted in other setting including deletion of eNOS or in disease states such as diabetes and hypercholesterolemia and this failure contributes greatly to morbidity u and mortality associated with these diseases. Nevertheless, the entire process is little understood and there are no currently successful approaches to deal with its defects in clinical settings. Understanding of molecular mechanism regulating arteriogenesis would be of great benefit to our understanding of pathobiology of major cardiovascular illnesses and to development of new therapeutic approaches to combat them. In this project we propose to focus on a newly discovered interaction between PI3K/Akt and ERK signaling pathways that appears to control arterial fate determination. Specifically we will 1) establish biological significance of Rafl SA-mediated decoupling of ERK and Akt signaling during development and in the normal vasculature; 2) Determine biological significance of Rafl SA-mediated decoupling of ERK and Akt signaling in impaired arteriogenesis settings and 3) dissect how endothelial dysfunction alters VEGFR2 signaling in hypercholesterolemic conditions and study whether ERK activation mitigates this defect. Taken together, this set of experiments will provide a comprehensive look at this critical arterial fate-determining signaling cascade.