Aortic Valve Development and Disease

Calcific aortic valve disease (CAVD) is an increasingly prevalent and life-threatening condition for which there are no clinically useful biological targets or therapeutic agents. Recent studies identified common signaling pathways present in both aortic valve formation and calcific aortic stenosis, but the understanding of how these signals are integrated and coordinated at the cell and tissue level is very limited. The cellular mechanisms controlling elongation, condensation, and matrix stratification of the valve primordial stage are clinically very important but are almost completely unknown.

These morphogenic and remodeling behaviors occur within a dynamic mechanical environment. Because of a lack of research tools, their effects are challenging to investigate. Cadherin-11 (CDH11), a cell-cell adhesion protein is a good option for regulating valve formation and homeostasis.

The preliminary data from Jonathan Butcher’s lab, Biomedical Engineering, demonstrate that deletion of CDH11 results in significant lethality during key valve remodeling periods. Conversely, valve specific overexpression of CDH11 is viable but with thickened aortic valves with regions of hypercellular interstitial aggregation and calcification typical of lesions seen in human CAVD.

Jonathan Butcher and his lab are testing the hypothesis that a tight range of CDH11 expression is essential for proper coordination of fetal valve cellularization, remodeling, and maturation for long-term homeostatic function. Their objectives are to determine the mechanobiological role of CDH11 in cellularization and remodeling of the embryonic aortic valve; test how CDH11 regulates postnatal valve remodeling and calcification; and test whether CDH11 rebalancing can rescue or prevent the development of aortic valve CHD and calcification. Butcher’s results will reveal a novel, tightly controlled and mechanically sensitive mechanism responsible for fetal valve maturation and postnatal homeostasis. 

Cornell Researchers

Funding Received

$1.5 Million spanning 4 years