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.

Recently, a team at Soochow University integrated 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, they developed an AD-specific organ-on-a-chip (OOC) system, which recapitulated key AD pathologies, including mitochondrial dysfunction, smooth muscle cell (SMC) phenotypic switching, and abnormal mechanotransduction.

“Deciphering how abnormal mechanotransduction drives medial degeneration is essential for elucidating AD pathogenesis and developing targeted therapies”, said lead author Mingliang Tang. “From a biomechanical perspective, we systematically reveal that WSS acts as a key driver in the initiation and progression of AD, and identify PIEZO1 as the core mechanosensor as well as a potential therapeutic target. Our work provides new insights into the mechanobiologymediated pathogenesis of AD and offers avenues for targeted prevention and treatment.” 

Tang is a distinguished professor in the Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Suzhou Medical College, Soochow University.

From patientspecific aortic modeling to OOC platform: FSIbased WSS simulation and experimental validation

The researchers discovered that the peak WSS in the aortic wall of patients with AD was significantly higher than that in the control group, approximately twice that of the controls (125.8 ± 42.2 Pa vs. 59.3 ± 9.8 Pa). Moreover, the peak WSS showed a significant positive correlation with the patient’s aortic root diameter (r = 0.387, p = 0.026), and this correlation was further enhanced in patients with coexisting hypertension (r = 0.462). 

To investigate how WSS drives cellular remodeling in AD, researchers designed an OOC system and applied different peak WSS values, demonstrating that it can markedly induce vascular SMC switch from a contractile to a synthetic/inflammatory phenotype, mimicking AD pathology.

Key role of WSS and PIEZO1 in aortic dissection pathology

RNASeq network analysis identified PIEZO1 as a central regulator of mitochondrial impairment, inflammatory responses, and SMC phenotypic transformation in AD. These findings were validated in clinical AD samples and recapitulated in the ADOOC system. Moreover, the mechanosensitive ion channel PIEZO1 was up-regulated at a peak WSS of 3.6 Pa, critically driving phenotypic switching of SMC and aberrant calcium signaling. Knockdown or antagonism of PIEZO1 reversed peakWSS pathology, while agonist Yoda1 recapitulated it. These results confirm the reliability and application potential of this OOC platform in simulating the pathological AD microenvironment, providing compelling evidence for PIEZO1-targeted therapy in vascular remodeling disorders. 

Sources: https://spj.science.org/doi/10.34133/research.1212