Microskeletal stiffness promotes aortic aneurysm by sustaining pathological vascular smooth muscle cell mechanosensation via Piezo1    

Abstract Mechanical overload of the vascular wall is a pathological hallmark of life-threatening abdominal aortic aneurysms (AAA). However, how this mechanical stress resonates at the unicellular level of vascular smooth muscle cells (VSMC) in AAA is undefined. Here, we combined novel ultrasound tweezers-based micromechancal system and single-cell RNA sequencing to map defective mechano-phenotype signature of VSMC niched in AAA. VSMC gradually adopted a mechanically solid-like state by upregulating cytoskeleton (CSK) crosslinker, α-actinin2, which stiffened VSMC cell membrane thereby directly powering the activity of mechano-sensory ion channel Piezo1 during AAA development. Theoretical modelling predicted that in AAA, such CSK alterations fueled cell membrane tension thereby blocking physiological mechanoallostatic responses of VSMC. Single-cell mechanical measurements and frequency spectrum analysis validated the mechanosensation deficiency in VSMC during AAA development. Our findings demonstrate that deviations of mechanosensation behaviors of VSMC is detrimental for AAA and identifies Piezo1 as a novel target to curb AAA onset.