Mechanobiology of cadherin-11 in calcific aortic valve disease

Abstract

Calcific aortic valve disease affects a quarter of those over 65 in the US alone. The only treatment is aortic valve replacement, but this intervention carries with it a high rate of morbidity and mortality and is often a procedure of last resort, leaving many to suffer the ill effects of worsening heart function as the disease progresses. Our lack of non-surgical interventions is a result of our lack of understanding the mechanisms driving calcific aortic valve disease. This work has studied the contributions of cadherin-11, a mechanosensitive cell-adhesion protein known to participate in various fibroblast-mediated diseases. We demonstrated that targeting cadherin-11 genetically or pharmacologically led to decreased maximum velocities across the aortic valve in a murine model of calcific aortic valve disease. We then investigated the intrinsic role of cadherin-11 in aortic valve interstitial cells, the population of cells that differentiate into myofibroblasts, which drive disease. We found that cadherin-11 is responsible for regulating a balance between intracellular, intercellular, and cell-substrate tension that can be overridden with disease initiators. We also better characterized a role of cadherin-11 in inflammation. Finally, we investigated differences between the interstitial cells of all cardiac valves to understand whether the intrinsic biology of these cells was different, or if the increased prevalence of disease in the aortic valve is primarily a result of its more demanding mechanical environment. Together, this work has furthered our knowledge of the mechanobiology of cadherin-11 in calcific aortic valve disease and the interstitial cells that mediate its progression.