Valvular endothelial cells and the mechanoregulation of valvular pathology

Abstract

Endothelial cells are critical mediators of haemodynamic forces and as such are important foci for initiation of vascular pathology. Valvular leaflets are also lined with endothelial cells, though a similar role in mechanosensing has not been demonstrated. Recent evidence has shown that valvular endothelial cells respond morphologically to shear stress, and several studies have implicated valvular endothelial dysfunction in the pathogenesis of disease. This review seeks to combine what is known about vascular and valvular haemodynamics, endothelial response to mechanical stimuli and the pathogenesis of valvular diseases to form a hypothesis as to how mechanical stimuli can initiate valvular endothelial dysfunction and disease progression. From this analysis, it appears that inflow surface-related bacterial/thrombotic vegetative endocarditis is a high shear-driven endothelial denudation phenomenon, while the outflow surface with its related calcific/atherosclerotic degeneration is a low/oscillatory shear-driven endothelial activation phenomenon. Further understanding of these mechanisms may help lead to earlier diagnostic tools and therapeutic strategies.

Figure 1

Valvular and vascular endothelial cell morphology in static and fluid flow environments. Insets depict F-actin filament organization (light grey) counterstained for cell nuclei (dark grey) at 40×. Phase contrast images at 20× magnification. PAEC, porcine aortic endothelial cells; PAVEC, porcine aortic valve endothelial cells.

Figure 2

Heatmap rendering of the clustered microarray data of valvular and vascular endothelial cells in static and fluid flow environments. Eleven different groups with unique expression profiles are identified A–K. Normalized log-transformed mean values for each cluster are plotted across conditions.

Figure 3

Mechanotransduction differences between valvular and vascular endothelial cells. Valvular endothelial cells align perpendicular to flow independent of PI-3 kinase, which is required for vascular endothelial cell alignment. Alignment of both endothelial cells is dependent on focal adhesion rearrangement. Modified from Butcher et al. (2004).

Figure 4

Schematic illustrating the potential roles for mechanical forces in the initiation of valvular pathologies. The inflow surface experiences high-magnitude pulsatile shear stresses and is the predominant location for thrombotic/bacterial endocarditis (A–G). The outflow surface experiences much lower, oscillatory shear stresses and is the predominant location for sclerotic/calcific lesion formation (1–6).