Cadherin-11 expression patterns in heart valves associate with key functions during embryonic cushion formation, valve maturation and calcification.

Proper fibroblast cell migration and differentiation are critical for valve formation and homeostasis, but uncontrolled myofibroblastic activation may precede osteogenic differentiation and calcification. Cadherin-11 (cad-11) is a cell-cell adhesion protein classically expressed at mesenchymal-osteoblast interfaces that participates in mesenchymal differentiation to osteochondral lineages. This suggests cad-11 may have an important role in heart valve development and pathogenesis, but its expression patterns in valves are largely unknown. In this study, we profiled the spatial and temporal expression patterns of cad-11 in embryonic chick and mouse heart development. We determined that cad-11 is expressed in both endocardial and mesenchymal cells of the atrioventricular and outflow tract cushions (pre-HH30/E14), but becomes restricted to the valve endocardial/endothelial cells during late fetal remodeling and throughout postnatal life. We then investigated changes in cad-11 expression in a murine aortic valve disease model (the ApoE(-/-)). Unlike wild-type mice, cad-11 becomes dramatically re-expressed in the interstitium. Similarly, in calcified human aortic valve leaflets, cad-11 loses endothelial confinement and becomes significantly re-expressed in the valve interstitium. Double labeling identified that 91% of myofibroblastic and 96% of osteoblastic cells in calcified aortic valves were also cad-11 positive. Collectively, our results suggest that cad-11 is important for proper embryonic cushion formation and remodeling, but may also participate in aortic valve pathogenesis if re-expressed in adulthood.