Investigation of Notch and nitric oxide signaling in the cardiovascular system

Notch signaling is evolutionarily conserved and regulates various developmental and pathological processes. We are interested in the role of Notch signaling in cardiac valve formation and postnatal vascular remodeling. The heart is the first organ to form in a developing embryo and a common site of congenital defects. Valvuloseptal defects are the most common of the cardiac anomalies seen in the newborn with a prevalence of 1-2% and are often a result of deregulated atrioventricular canal (AVC) formation. The process of endothelial-to-mesenchymal-transition (EndMT) is required for the growth and maturation of the AVC and Notch signaling has been shown to induce this process. In chapter 3, we identify a novel link between Notch and Nitric Oxide (NO) signaling during EndMT. We show that Notch-activation directly induces GUCY1A3 and GUCY1B3, the soluble guanylyl cyclase that forms the heterodimeric NO receptor, during EndMT. We also show that Notch-induced expression and secretion of the TGFβ family member, Activin A, results in increased NO production via a PI3-kinase/Akt signaling mechanism. Paracrine activation of NO signaling by Activin A contributes to early onset of EndMT in the developing AVC. Functional arteries are essential for restoring blood flow and tissue regeneration in response to hypoxia, ischemia, or wound healing. Arterial obstruction can cause distal tissue ischemia and requires rapid reperfusion to limit tissue necrosis. Ischemia recovery requires two processes: angiogenesis (capillary sprouting) and arteriogenesis (expansion of existing vessels secondary to mechanical stress or chemical stimuli). Arteriogenesis involves two phases: a rapid vasodilatory phase followed by vascular expansion and remodeling. In chapter 4, we examine the relationship of endothelial Notch signaling and arteriogenesis using a hindlimb ischemia model. As the link between Notch and NO signaling unfolded in the heart study, we turned our attention to the NO pathway in the initial phase of arteriogenesis – vasodilation. The data presented in this dissertation defines a novel link between Notch signaling and NO signaling in the cardiovascular system and may help to explain Notch-induced EndMT in other pathologies.Medicine, Faculty ofMedicine, Department ofExperimental Medicine, Division ofGraduat