PROJECT SUMMARY Fluid shear stress-dependent vessel remodeling is an essential regulatory mechanism in embryonic development and in adult vascular homeostasis where it optimizes blood flow to target tissues. Conversely, un- or mis-regulated remodeling results in vascular malformations, while poor remodeling is a key aspect of blood flow restriction in coronary and periphery artery disease. Our preliminary data reveal the existence of a regulatory network with two mutually inhibitory states, one associated with vessel stability and one with physiological outward remodeling or pathological AVM formation. These results allow us to propose a unifying hypothesis that links physiological and pathological remodeling, and suggest the existence of control points that can be manipulated to either increase or decrease vascular lumen diameter. The project aims to elucidate these regulatory mechanisms and then harness these new insights to investigate their relevance to vascular development, to identify therapeutic targets for HHT patients who suffer from excessive pathological remodeling, and identify therapeutic targets for coronary and peripheral artery disease patients where physiological remodeling is impaired. We will define the molecular basis of this novel EC shear stress mechanism, determine its biological role and develop and test therapeutic applications based on this knowledge.