Title: Developmental mechanisms of aortic valve disease

Biography:

Bin Zhou has received his MD in 1986 from Nanjing Medical University, China and Fellowship training in Medicine/Cardiology between 1986 and 1991 from the First Affiliated Hospital of Nanjing Medical University. He has then received his PhD in 1998 from the Department of Experimental Medicine and Pathobiology of the University of Toronto, Canada, in the laboratory of Professor Marlene Rabinovitch, where he studied vascular stenosis. In 2002, he was recruited to Vanderbilt University as an Assistant Professor of Pediatrics (Cardiology) to establish his independent research program. He was recruited to Albert Einstein College of Medicine in 2008 as an Associate Professor of Genetics, Pediatrics and Medicine (Cardiology) and promoted to Full Professor in 2013.

Abstract

Normal aortic valve is composed of valve endothelial cells (VEC) and valve interstitial cells (VIC). VIC is the major cell population and has distinct embryonic origins in the endocardium and cardiac neural crest cells. Cell signaling between VEC and VIC plays critical roles in aortic valve morphogenesis. Disruption of major cell signaling pathways results in aortic valve malformations, including bicuspid aortic valve. Bicuspid aortic valve is a common congenital heart valve disease that may lead to calcific aortic valve disease, but there is currently no effective medical treatment for this beyond surgical replacement. Human studies have identified that NOTCH1 mutations cause bicuspid aortic valve. Here we present our findings from mouse studies demonstrating that NOTCH1-Tnfa signaling is required for development and homeostasis of aortic valve. We generated and characterized mouse models with conditionally altered Notch signaling in endothelial or interstitial cells of aortic valve. Mice with inactivation of NOTCH1 signaling in VEC developed bicuspid aortic valve and valve stenosis. NOTCH1 signaling in VEC was required for repressing proliferation and activating apoptosis of VIC after endothelial-to-mesenchymal transformation (EMT). We showed that NOTCH1 signaling regulated Tnfa expression in vivo and Tnfa signaling was necessary for apoptosis of VIC and post-EMT development of aortic valve. We have now met the need of critical animal models and shown that NOTCH1-Tnfa signaling balances proliferation and apoptosis for post-EMT development of aortic valve. Our results suggest that mutations in its components may lead to bicuspid aortic valve and valve stenosis in humans.