Dynamic Blood Flow Modulates Endothelial Mitochondrial Redox States and Vascular Repair

Temporal and spatial variations in shear stress are intimately linked with vascular metabolic effects. Fluid shear stress plays a major role in regulating endothelial homeostasis, dysfunction, and vasculogenesis. First study we demonstrated atherogenic oscillatory shear stress (OSS) induced mitochondrial superoxide (mtO2•--) production via NADPH oxidase and c-Jun NH2-terminal kinase (JNK) signaling. Next we revealed that OSS-mediated oxidative stress and JNK activation induced autophagy but impaired autophagic flux to promote mtO2•-- production, mtDNA damage, and mitochondrial dysfunction in the disturbed flow-exposed regions. Then we demonstrated rapid and irregular pacing reduced intravascular shear stress (ISS) with implications to endothelial response modulation. Lastly, we investigated whether shear stress activated angiopoietin-2 (Ang-2) via the canonical Wnt signaling pathway with implications in vascular endothelial repair. Collectively, we characterized the mechanisms whereby shear stress modulates these effects.