Association between shear stress and platelet-derived transforming growth factor-β1 release and activation in animal models of aortic valve stenosis.

OBJECTIVE Aortic valve stenosis (AS) is characterized by fibrosis and calcification of valves leading to aortic valve narrowing, resulting in high wall shear stress across the valves. We previously demonstrated that high shear stress can activate platelet-derived transforming growth factor-β1 (TGF-β1), a cytokine that induces fibrosis and calcification. The aim of this study was to investigate the role of shear-induced platelet release of TGF-β1 and its activation in AS. APPROACH AND RESULTS We studied hypercholesterolemic Ldlr(-/-)Apob(100/100)/Mttp(fl/fl)/Mx1Cre(+/+) (Reversa) mice that develop AS on Western diet and a surgical ascending aortic constriction mouse model that acutely simulates the hemodynamics of AS to study shear-induced platelet TGF-β1 release and activation. Reversa mice on Western diet for 6 months had thickening of the aortic valves, increased wall shear stress, and increased plasma TGF-β1 levels. There were weak and moderate correlations between wall shear stress and TGF-β1 levels in the progression and reversed Reversa groups and a stronger correlation in the ascending aortic constriction model in wild-type mice but not in mice with a targeted deletion of megakaryocyte and platelet TGF-β1 (Tgfb1(flox)). Plasma total TGF-β1 levels correlated with collagen deposition in the stenotic valves in Reversa mice. Although active TGF-β1 levels were too low to be measured directly, we found (1) canonical TGF-β1 (phosphorylated small mothers against decapentaplegic 2/3) signaling in the leukocytes and canonical and noncanonical (phosphorylated extracellular signal-regulated kinases 1/2) TGF-β1 signaling in aortic valves of Reversa mice on a Western diet, and (2) TGF-β1 signaling of both pathways in the ascending aortic constriction stenotic area in wild-type but not Tgfb1(flox) mice. CONCLUSIONS Shear-induced, platelet-derived TGF-β1 activation may contribute to AS.