Mechanopriming by vascular stiffness and disturbed flow drive pathological reprogramming in atherosclerosisMechanisms of Vascular Stiffness Link to Atherosclerosis Development

Atherosclerosis exhibits a distinct focal distribution at arterial bifurcations and curvatures, underscoring that systemic risk factors alone are insufficient to fully elucidate its pathogenesis. The coupling of local fluid shear stress—particularly disturbed flow (DF) and oscillatory shear stress (OSS)—with vascular wall stiffness constitutes the core mechanical driver of site-specific plaque progression. This narrative review systematically elucidates the cutting-edge molecular mechanisms of vascular wall-mediated “mechanopriming” and endothelial mechanotransduction. We highlight how the Piezo1 ion channel and the 5-HT1B receptor act as “coincidence detectors,” precisely integrating fluid shear stress and matrix stiffness signals to subsequently activate central signaling hubs such as YAP and c-REL. The dysregulation of these mechanopathways not only triggers pathological reprogramming of endothelial cells—including cGAS-STING-mediated deep senescence, NLRP3-driven pyroptosis, and endothelial-to-mesenchymal transition (EndoMT)—but also impairs RBPJ-epigenetically regulated macrophage efferocytosis and drives pathological matrix remodeling by smooth muscle cells and fibroblasts via complex transcellular communication networks. Clinically, the fusion of multimodal imaging with computational fluid dynamics (CFD), alongside emerging ultrafast ultrasound vector flow imaging, has pioneered novel avenues for the high-fidelity in vivo quantification of wall shear stress (WSS). Finally, we critically evaluate current research limitations and prospectively discuss frontier shear stress-targeted therapeutic strategies—such as “mechanodrugs,” biomimetic nanodelivery, and hemodynamic stent optimization—proposing a novel precision cardiovascular medicine framework that formally incorporates localized hemodynamic parameters into established clinical risk stratification algorithms like the ASCVD and SCORE2 models.