Piezo-type mechanosensitive ion channel component 1 (PIEZO1) is upregulated in peripheral arterial disease (PAD) and a novel murine PAD model

Objective The objectives of this work are to: define murine femoral artery stiffening with age and the modifiability of this process by exercise; impose peripheral arterial disease (PAD) hemodynamics on murine femoral arteries and to deliver focal atherosclerotic plaque to femoral arteries; and test piezo-type mechanosensitive ion channel component 1 (PIEZO1) expression in human and murine femoral arteries of PAD. Methods We used a running wheel to exercise young and old S129 mice and biomechanical testing to quantify changes in arterial stiffness. We created a novel partial femoral artery ligation (PFL) model to impose PAD hemodynamics via low wall shear stress (WSS) to create a flow-mediated model of arterial aging in femoral arteries. In vivo mechanics were defined with ultrasound. Ex vivo arteries underwent biaxial tests. Atherogenic conditions were induced using PCSK9 infection and a high-fat diet. Arterial remodeling and PIEZO1 expression were quantified by histology. Results Femoral arteries are naturally stiffer than carotid arteries; both stiffen further with aging, but exercise improved compliance in old femoral arteries. PFL imposed low WSS and stiffening, similar to that seen in aging. Under atherogenic conditions, PFL delivered focal atherosclerotic plaques in femoral arteries. Low WSS increased PIEZO1 expression in femoral arteries (∼1.8× in endothelial cells, ∼2.4× in smooth muscle cells, and ∼2.8× in macrophages). Human PAD arteries with high-grade stenosis validated increased PIEZO1 mRNA (∼1.83×). Conclusions Femoral artery mechanics differ significantly from the carotid artery but can be modified by exercise. This PFL model confers arterial stiffness, and under atherogenic conditions, delivers focal femoral atherosclerotic plaque. PIEZO1 expression increases in both PFL-treated mouse femoral arteries and human PAD arteries with severe stenosis, supporting this as a translational target for PAD. Clinical Relevance Peripheral artery disease (PAD) is the third most common atherosclerotic bed. PAD is associated with increased risk of limb loss and death, but the mechanisms driving site-specific arterial remodeling in PAD remain unclear. This work uniquely creates a model of PAD that incorporates arterial stiffening via aging and flow disturbances and inducing atherosclerotic plaque into the murine femoral artery. By comparing murine femoral arteries with PAD arteries, piezo-type mechanosensitive ion channel component 1 (PIEZO1) was discovered as key mediator linking PAD blood flow and stiffening to untoward changes in endothelial cells, smooth muscle cells, and macrophages within femoral arteries. Targeted modulation of PIEZO1 activity provide PAD-centric therapeutic strategies and help promote the vascular health, life, and limb outcomes in patients with PAD.