High Fluid Shear Stress and Spatial Shear Stress Gradients Affect Endothelial Proliferation, Survival, and Alignment

Abstract

Cerebral aneurysms develop near bifurcation apices, where complex hemodynamics occur: Flow impinges on the apex, accelerates into branches, then slows again distally, creating high wall shear stress (WSS) and positive and negative spatial gradients in WSS (WSSG). Endothelial responses to these kinds of high WSS hemodynamic environments are not well characterized. We examined endothelial cells (ECs) under elevated WSS and positive and negative WSSG using a flow chamber with constant-height channels to create regions of uniform WSS and converging and diverging channels to create positive and negative WSSG, respectively. Cultured bovine aortic ECs were subjected to 3.5 and 28.4 Pa with and without WSSG for 24 and 36 h. High WSS inhibited EC alignment to flow, increased EC proliferation assessed by bromodeoxyuridine incorporation, and increased apoptosis determined by terminal deoxynu-cleotidyl transferase dUTP-mediated nick-end labeling. These responses to high WSS were either accentuated or ameliorated by WSSG: Positive WSSG (+980 Pa/m) inhibited alignment and stimulated proliferation and apoptosis, whereas negative WSSG (−1120 Pa/m) promoted alignment and suppressed proliferation and apoptosis. These results demonstrate that ECs discriminate between positive and negative WSSG under high WSS conditions. EC responses to positive WSSG may contribute to pathogenic remodeling that occurs at bifurcations preceding aneurysm formation.

Flow dynamics control the location of sprouting and direct elongation during developmental angiogenesis

“…It is possible that both extremes are permissive to sprouting. Both low (<10 dyn/cm 2 ) and pathologically high shear stress (>50 dyn/cm 2 ) result in increased cell turnover by stimulating both apoptosis (Davies et al, 1986;Dolan et al, 2011) and proliferation (Davies et al, 1986;Metaxa et al, 2008;Sho et al, 2003). Physiological levels of shear stress, by contrast, induce endothelial cell quiescence.…”

“…Whether vorticity affects endothelial cells has never been studied, but it seems improbable as vorticity is not a force but rather a measure of the rate of rotation of the fluid elements. The endothelium is a continuous layer connected by gap junctions and endothelial cells can sense gradients in shear stress (Dolan et al, 2011;Rouleau et al, 2010). Points at which there is a change in sign in the vorticity are surrounded by shear stress vectors on either side that are in opposite directions.…”

Bicuspid aortic valve hemodynamics does not promote remodeling in porcine aortic wall concavity

“…Although relationships between WSS abnormalities and biological perturbations in the aortic endothelium have been previously evidenced [51][52][53][54] , more work needs to be done to isolate the impact of hemodynamic stress abnormalities on tissue remodeling. The results collected from the present study combined with those from our previous study [35] on the local effects of TAV and LR-BAV AA hemodynamic stresses on AA remodeling suggest the susceptibility of BAV hemodynamic stresses to mediate aortic medial degradation on the diseaseprone wall convexity, while sparing the wall concavity.…”

Differential gene expression by endothelial cells under positive and negative streamwise gradients of high wall shear stress

“…1) was used to impose high levels of shear stress and positive and negative WSSG on cultured ECs in timematched experiments as previously described (7). In brief, flow entered between two parallel surfaces (Fig.…”