Mechanobiology of the Aortic Valve Interstitial Cell

The aortic valve (AV) is essentially a passive organ that permits unidirectional blood flow from the left ventricle to the systemic circulation and prohibits regurgitant flow during diastole. The extracellular matrix (ECM) of the AV leaflet is tri-layered with type I collagen making up the fibrosa layer (aortic side), glycosaminoglycans constituting the middle spongiosa layer, and elastin fibers largely in the ventricularis layer. Each component of the ECM is synthesized, enzymatically degraded, and maintained by the resident population of interstitial cells (AVICs) dispersed throughout the leaflet. The AVICs have been recognized as a heterogeneous mix of cells which include fibroblasts, smooth muscle cells, and myofibroblasts, which have characteristics of both fibroblasts and smooth muscle cells but are unique from each. The hypothesis of this dissertation is that the phenotype and function of the AVIC is predicated on the mechanical environment in which it resides, and during times of activated remodeling (increased myofibroblasts), the mechanobiological response of the AVIC may be contributor to changes in valvular tissue integrity. To test this hypothesis, we examine 1) the mechanical properties of the AVIC and the correlation to biosynthesis, 2) the strong connectivity of the AVIC to the ECM which is demonstrated by the AVICs ability to generate tissue-level forces due to contraction, 3) potential tissue remodeling capabilities of the AVIC via collagen gel contraction, 4) the micromechanics of the AVIC to increasing strain levels, and 5) synergistic response of the in situ AVIC to TGF-â1 and cyclic strain.Results from this work highlight the mechanobiological properties of the AVIC myofibroblast phenotype and its role in valvular tissue homeostasis, remodeling, and dysfunction. Moreover, these results demonstrate the unexamined mechanical properties of the AVIC and the strong correlate with ECM biosynthesis. As the AVIC is situated in a tissue with large strains and varying modes of deformation, the mechanical properties of the cell are likely prominent in their function. We believe that these results will add to the growing body of AVIC literature and further believe that our focus on the AVIC micro-mechanical environment will be very relevant to understanding the mechanobiologic function of the AVIC