Adult Valve Disease Mechanisms

Thrust 2: Endothelial-Interstitial Cell Interactions in Valve Homeostasis and Disease

The only treatment for heart valve disease is prosthetic valve replacement. There remain no clinically useful biologically based diagnostics specific to valve disease or biologically based therapies. This is largely due to the limited understanding of how the resident endothelial and interstitial cells of the valve work together to appropriately maintain function. The vast majority of valve biology research focuses on calcification by the valve interstitial cell (VIC). We however have also focused on the valve endothelial cells (VEC), which mediate all biochemical and hemodynamic signals from the blood, and are therefore critical to understand for effecting therapy. VEC have vastly different gene expressions and cellular behaviors than arterial endothelium. Inflammatory activation of VEC is present at the earliest stages of valve disease, but the pathological consequences of this are not known. In advanced stages, VEC monolayers are disrupted at sites of calcific lesions. Untangling these interactions is challenging with purely genetic approaches that necessarily affect both VEC and VIC phenotype the same. Furthermore, these heterogeneous cellular interactions take place within a mechanically active 3D microenvironment that cannot be ignored.

Our lab has been tackling these challenges for nearly 20 years. We have made pioneering discoveries into valvular endothelial mechanobiology and their regulation of underlying interstitial cell phenotype. We develop and apply innovative in vitro culture systems to dissect shared and unique mechanisms of endothelial and interstitial cell behavior. These are integrated into novel bioreactors that apply physiological and pathological mechanical forces to elucidate their role in valvular interactions. We further employ genetic manipulation and live cell tracking to elaborate how cell specific molecular regulation affect homeostasis and disease pathogenesis. Together, these approaches help us better understand how these cells respond to changes in their environment, hopefully translating to biologically based strategies to diagnose and prevent valve deterioration, delaying or eliminating the need for prosthetic replacement.

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