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

Weiyi Qian, Tarik Hadi, Michele Silvestro, Xiao Ma, Cristobal F. Rivera, Apratim Bajpai, Rui Li, Zijing Zhang, Hengdong Qu, Rayan Sleiman Tellaoui, Annanina Corsica, Ariadne L. Zias, Karan Garg, Thomas Maldonado, Bhama Ramkhelawon () and Weiqiang Chen ()
Additional contact information
Weiyi Qian: New York University
Tarik Hadi: New York University Langone Medical Center
Michele Silvestro: New York University Langone Medical Center
Xiao Ma: New York University
Cristobal F. Rivera: New York University Langone Medical Center
Apratim Bajpai: New York University
Rui Li: New York University
Zijing Zhang: New York University
Hengdong Qu: New York University Langone Medical Center
Rayan Sleiman Tellaoui: New York University Langone Medical Center
Annanina Corsica: New York University Langone Medical Center
Ariadne L. Zias: New York University Langone Medical Center
Karan Garg: New York University Langone Medical Center
Thomas Maldonado: New York University Langone Medical Center
Bhama Ramkhelawon: New York University Langone Medical Center
Weiqiang Chen: New York University

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: 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) is undefined. Here we show defective mechano-phenotype signatures of VSMC in AAA measured with ultrasound tweezers-based micromechanical system and single-cell RNA sequencing technique. Theoretical modelling predicts that cytoskeleton alterations fuel cell membrane tension of VSMC, thereby modulating their mechanoallostatic responses which are validated by live micromechanical measurements. Mechanistically, VSMC gradually adopt a mechanically solid-like state by upregulating cytoskeleton crosslinker, α-actinin2, in the presence of AAA-promoting signal, Netrin-1, thereby directly powering the activity of mechanosensory ion channel Piezo1. Inhibition of Piezo1 prevents mice from developing AAA by alleviating pathological vascular remodeling. Our findings demonstrate that deviations of mechanosensation behaviors of VSMC is detrimental for AAA and identifies Piezo1 as a novel culprit of mechanically fatigued aorta in AAA.

Date: 2022
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DOI: 10.1038/s41467-021-27874-5

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