Calcific aortic valve disease (CAVD) is an increasingly prevalent and life-threatening condition for which there are currently no clinically useful biological targets or therapeutic agents. Several compelling recent studies have identified common signaling pathways present in both aortic valve formation and calcific aortic stenosis, but our 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 primordia are of highest clinical importance but are almost completely unknown. Further complicating matters is that these morphogenic and remodeling behaviors occur within a dynamic mechanical environment, the effects of which have been challenging to investigate due to a lack of research tools. Cadherin-11 is a cell-cell adhesion protein that regulates of collective mesenchymal cell migrations and their subsequent differentiation to osteogenic lineages, making it an attractive candidate for regulating valve formation and homeostasis. Cadherin-11 is strongly and specifically expressed in both the endocardium and mesenchyme of the endocardial cushions, but progressively downgrades in the mesenchyme as cushions elongate into valves. The preliminary data in this proposal demonstrates that deletion of cadherin-11 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. This proposal will test the hypothesis that a tight range of Cadherin-11 expression is essential for proper coordination of fetal valve cellularization, remodeling, and maturation for long-term homeostatic function.
The first aim of the proposal will be to determine the mechanobiological role of cadherin- 11 in cellularization and remodeling of the embryonic aortic valve.
Aim 2 will test how cadherin-11 regulates postnatal valve remodeling and calcification.
Aim 3 of the proposal will test whether cadherin-11 rebalancing can rescue and/or prevent the development of aortic valve CHD and/or calcification. The results of this study will elaborate a novel tightly controlled and mechanically sensitive mechanism responsible for fetal valve maturation and postnatal homeostasis. The combinatorial approach presented will accelerate the development of molecular strategies that diagnose and control clinically accessible functional deficiencies in valve development and calcification risk.
Several molecular mechanisms guiding malformation of the aortic valve appear reactivated during adult calcific valve degeneration. This proposal tests how cadherin-mediated adhesive transitions mediate cellular decisions to create mature aortic valves and maintain tissue homeostasis. Novel conditional mouse genetics models will be combined with in vitro culture systems to dissect how each contributes to mechanical sensation based tissue remodeling in the fetal and adult aortic valve.
