Shear type and magnitude affect aortic valve endothelial cell morphology, orientation, and differentiation.

Valvular endothelial cells line the outer layer of heart valves and can withstand shear forces caused by blood flow. In contrast to vascular endothelial cells, there is limited amount of research over valvular endothelial cells. For this reason, the exact physiologic behavior of valvular endothelial cells is unclear. Prior studies have concluded that valvular endothelial cells align perpendicularly to the direction of blood flow, while vascular endothelial cells align parallel to blood flow. Other studies have suggested that different ranges of shear stress uniquely impact the behavior of valvular endothelial cells. The goal of this study was to characterize the response of valvular endothelial cell under different types, magnitudes, and durations of shear stress. In this work, the results demonstrated that with increased shear rate and duration of exposure, valvular endothelial cells no longer possessed the traditional cuboidal morphology. Instead through the change in cell circularity and aspect ratio, valvular endothelial cells aligned in an organized manner. In addition, different forms of shear exposure caused the area and circularity of valvular endothelial cells to decrease while inducing mesenchymal transformation validated through αSMA and TGFß1 expression. This is the first investigation showing that valvular endothelial cells alignment is not as straightforward as once thought (perpendicular to flow). Different types and magnitudes of shear induce different local behaviors. This is also the first demonstration of valvular endothelial cells undergoing EndMT without chemical inducers on a soft surface in vitro. Findings from this study provide insights to understanding the pathophysiology of valvular endothelial cells which can potentially propel future artificial engineered heart valves.

The tricuspid valve also maladapts as shown in sheep with biventricular heart failure.

Over 1.6 million Americans suffer from significant tricuspid valve leakage. In most cases this leakage is designated as secondary. Thus, valve dysfunction is assumed to be due to valve-extrinsic factors. We challenge this paradigm and hypothesize that the tricuspid valve maladapts in those patients rendering the valve at least partially culpable for its dysfunction. As a first step in testing this hypothesis, we set out to demonstrate that the tricuspid valve maladapts in disease. To this end, we induced biventricular heart failure in sheep that developed tricuspid valve leakage. In the anterior leaflets of those animals, we investigated maladaptation on multiple scales. We demonstrated alterations on the protein and cell-level, leading to tissue growth, thickening, and stiffening. These data provide a new perspective on a poorly understood, yet highly prevalent disease. Our findings may motivate novel therapy options for many currently untreated patients with leaky tricuspid valves.

The effect of physiological stretch and the valvular endothelium on mitral valve proteomes.

IMPACT STATEMENT: This work is important to the field of heart valve pathophysiology as it provides new insights into molecular markers of mechanically induced valvular degeneration as well as the protective role of the valvular endothelium. These discoveries reported here advance our current knowledge of the valvular endothelium and how its removal essentially takes valve leaflets into an environmental shock. In addition, it shows that static conditions represent a mild pathological state for valve leaflets, while 10% cyclic stretch provides valvular cell quiescence. These findings impact the field by informing disease stages and by providing potential new drug targets to reverse or slow down valvular change before it affects cardiac function.