In conclusion, we demonstrate that peripheral small arteries from CADASIL patients exhibit endothelial dysfunction, impaired endothelium-independent vasorelaxation, hyporeactivity, and altered structural and mechanical properties, processes associated with altered VSMC growth and cytoskeletal reorganization and perturbed vascular signaling involving Notch3 gain of function, Nox5-derived ROS, ER stress, and Rho kinase activation. The gene discussed is NOTCH3; the disease is endothelial dysfunction.