Wall Shear Stress as a Modulator of Aortic Dissection: Mechanistic Insights from Patient-Specific Modeling and Organ-on-a-Chip Validation

Aortic dissection (AD) is a life-threatening vascular disorder driven by complex biomechanical forces, among which wall shear stress (WSS), the tangential frictional force from blood flow, plays a critical but poorly understood role. Direct clinical measurement of WSS remains challenging, limiting insights into its mechanistic links to AD pathogenesis. Here, we combined computational fluid dynamics with fluid–structure interaction modeling to quantify WSS in 33 AD patients and 25 controls, revealing a 2-fold higher peak WSS in AD patients that strongly correlated with AD initiation and progression. To mimic AD-relevant WSS microenvironments, we developed an AD-specific organ-on-a-chip (AD-OOC) system, which recapitulated key AD pathologies, including mitochondrial dysfunction, smooth muscle cell (SMC) phenotypic switching, and abnormal mechanotransduction. Mechanistically, RNA sequencing of human aortic tissues and functional validation in AD-OOC identified Piezo-type mechanosensitive ion channel component 1 (PIEZO1) as the pivotal mechanosensitive ion channel mediating WSS-induced SMC transition from a contractile to a synthetic/inflammatory phenotype. Silencing PIEZO1 reversed this pathological switch, confirming its regulatory role. These findings establish WSS as a critical biomechanical driver of AD and identify PIEZO1 as a promising therapeutic target for vascular remodeling disorders, while the AD-OOC platform offers a powerful tool.