Role of Pathologic Shear Stress Alterations in Aortic Valve Endothelial Activation
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Calcific aortic stenosis is the most common aortic valve (AV) disease and is triggered by an active inflammatory process involving endothelial activation and cytokine expression. Interfacing between the leaflet and the surrounding blood flow, shear stress is presumed to play an important role in endothelial injury. This study investigated the hypothesis that pathologic alterations in shear stress magnitude contribute to valvular endothelial activation via BMP-4- and TGF-β1-dependent mechanisms. The fibrosa of porcine AV leaflets was subjected to physiologic, sub-physiologic and supra-physiologic magnitudes of native oscillatory shear stress for 48 h. Endothelial activation was assessed via immunohistochemistry in terms of ICAM-1 and VCAM-1 expressions. Cytokine expression was investigated in terms of BMP-4 and TGF-β1. Pro- and anti-osteogenic media were used to characterize the role of those cytokines in the shear stress-induced pathological response. Supra-physiologic shear stress increased the expression of all biomarkers in a shear stress magnitude-dependent manner. In contrast, neither physiologic nor sub-physiologic shear stress elicited a pro-inflammatory response. While BMP-4 inhibition and supplementation had limited effects on endothelial activation, TGF-β1 supplementation increased the overall leaflet pro-inflammatory state and TGF-β1 inhibition reduced endothelial activation in response to elevated shear stress. Combined TGF-β1 and BMP-4 inhibition completely suppressed shear stress-induced endothelial activation. The results demonstrate that elevated shear stress activates the valvular endothelium on the fibrosa via a BMP-4- and TGF-β1-dependent pathway. The suggested synergy between those cytokines also provides new insights into the transduction of valvular hemodynamic alterations into a pathological response.