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.
Highlights
Mechanical overload of the vascular wall is a pathological hallmark of life-threatening abdominal aortic aneurysms (AAA)
Aortic pulse wave velocity (PWV) revealed that the vessel wall stiffness was incrementally increased in AAA compared to controls (Fig. 1b), consistent with a previous report[25]
We have previously demonstrated that the conditional deletion of Netrin-1 in monocyte and macrophages Ntn1flox/floxLysMcre+/− (NKO) protected mice from developing AAA compared to Ntn1flox/flox mice (WT) when challenged to AAA via Proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) overexpression combined with Western diet and Angiotensin II (Ang II) infusion[23] (Fig. 5a)
Summary
Mechanical overload of the vascular wall is a pathological hallmark of life-threatening abdominal aortic aneurysms (AAA). How this mechanical stress resonates at the unicellular level of vascular smooth muscle cells (VSMC) is undefined. We demonstrated that Netrin-1 was released from transmural macrophages and promoted AAA by sustaining downstream Ca2+ signals necessary to stimulate matrix degrading metalloproteinase MMP3 in VSMC23. This suggested that the pathological proteolytic switch of VSMC triggered by Netrin-1 in AAA could be driven by microskeletal alterations via Piezo[1]. Our study reveals a molecular connection between defective mechanosensation and pathological vascular remodeling and attribute the overactivation of Piezo[1] as a critical mediator of these effects
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