Mechanoregulation of aortic valvular interstitial cell life and death

Valvular interstitial cells (VICs) are the major cell type within aortic valve leaflets. VICs are able to exhibit a spectrum of phenotype characteristics including those of fibroblasts, smooth muscle cells, and myofibroblasts. VICs are responsible for valve maintenance and repair, yet excessive persistence of the myofibroblast phenotype is implicated in a number of valve diseases, including calcific aortic valve disease and fibrosis. Despite the prevalence of these diseases, the stimuli regulating the transition to the activated myofibroblast state and reversal to quiescent fibroblast and/or induction of apoptosis are not fully understood. The purpose of this article is to review in vitro studies that have contributed to the current understanding of mechanical regulation of VIC phenotype and fate. In particular, we have focused on studies utilizing advanced in vitro systems that allow modulation and measurement of cell tension and cell-generated forces in two-dimensional and three-dimensional cultures. In addition, we discuss the importance of cell tension in phenotype modulation and how cytoskeletal tension may contribute to aggregation and calcification. Future directions of pharmaceutical development aimed at reducing VIC cytoskeletal tension are also highlighted.