Endothelial protocadherins in vascular development and disease

PROJECT SUMMARY Transcription factors Klf2 and 4 are strongly induced in vascular endothelial cells (ECs) by fluid shear stress from blood flow, where they confer vascular stability and suppress the inflammatory pathways and genes responsible for atherosclerosis and other diseases that involve vascular inflammation. This application is based on our recent discovery that gamma protocadherins (Pcdhg) block Notch-dependent transcription and thus suppress expression Klf2/4 in ECs, which facilitates vascular inflammation and disease. Pcdhg knockout in endothelial cells limits atherosclerosis in mice and alters vascular morphogenesis in the postnatal retina. Based on our findings, we hypothesize that Pcdhg is a key regulator of vascular stability and resilience that contributes to vascular morphogenesis but whose inhibition provides a novel means of treating vascular inflammation without compromising host defense against pathogens. To test these hypotheses, we propose to: 1) Determine the effects in mice of knocking out the Pcdhg cluster in ECs or inhibiting the key isoform Pcdhga9, examining multiple models of vascular inflammation. 2) Elucidate the mechanism by which Pcdhg controls Klf2/4 expression, focusing on interactions with the Notch pathway. 3) Characterize the effects of EC Pcdhg knockout on angiogenesis and arteriogenesis in the postnatal retina and determine the molecular mechanisms of observed effects.