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

• Published in: Nature communications 2022-01, Vol.13 (1), p.512-512, Article 512
• Main Authors: Qian, Weiyi, Hadi, Tarik, Silvestro, Michele, Ma, Xiao, Rivera, Cristobal F., Bajpai, Apratim, Li, Rui, Zhang, Zijing, Qu, Hengdong, Tellaoui, Rayan Sleiman, Corsica, Annanina, Zias, Ariadne L., Garg, Karan, Maldonado, Thomas, Ramkhelawon, Bhama, Chen, Weiqiang
• Format: Article
• Language: English
• Subjects: 147/3; 631/1647/2204; 631/57; 639/166/985; 692/699/75/593/1287; 9/10; Aneurysm; Animals; Aorta; Aorta, Abdominal; Aortic Aneurysm - metabolism; Aortic Aneurysm - pathology; Aortic Aneurysm, Abdominal - metabolism; Aortic aneurysms; Biomedical Engineering; Biophysical Phenomena; Cell membranes; Cytoskeleton; Disease Models, Animal; Fuel cells; Fuel technology; Gene sequencing; Humanities and Social Sciences; Ion channels; Ion Channels - genetics; Ion Channels - metabolism; Male; Mechanotransduction; Mice; Mice, Inbred C57BL; multidisciplinary; Muscle, Smooth, Vascular - metabolism; Muscles; Myocytes, Smooth Muscle - metabolism; Netrin-1; Netrin-1 - metabolism; Phenotype; Phenotypes; Science; Science (multidisciplinary); Smooth muscle; Stiffness; Stress, Mechanical; Vascular Remodeling
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-27874-5

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. Mechanobiological signals have been reported to contribute to abdominal aortic aneurysm (AAA) development. Here the authors report that the microskeletal stiffness and a Piezo1-mediated mechanism influence vascular smooth muscle cell mechanosensation and AAA disease development.