Piezo1 channels sense whole body physical activity to reset cardiovascular homeostasis and enhance performance

Abstract

Mammalian biology adapts to physical activity but the molecular mechanisms sensing the activity remain enigmatic. Recent studies have revealed how Piezo1 protein senses mechanical force to enable vascular development. Here, we address Piezo1 in adult endothelium, the major control site in physical activity. Mice without endothelial Piezo1 lack obvious phenotype but close inspection reveals a specific effect on endothelium-dependent relaxation in mesenteric resistance artery. Strikingly, the Piezo1 is required for elevated blood pressure during whole body physical activity but not blood pressure during inactivity. Piezo1 is responsible for flow-sensitive non-inactivating non-selective cationic channels which depolarize the membrane potential. As fluid flow increases, depolarization increases to activate voltage-gated Ca2+ channels in the adjacent vascular smooth muscle cells, causing vasoconstriction. Physical performance is compromised in mice which lack endothelial Piezo1 and there is weight loss after sustained activity. The data suggest that Piezo1 channels sense physical activity to advantageously reset vascular control.

Endothelial Piezo1 channels as sensors of exercise

“…) and we went on to show that endogenous channels of the endothelium were activated by shear stress in excised outside‐out cell‐free membrane patches, suggesting that the channels are likely to be direct sensors of shear stress or a closely linked force (Rode et al . ).…”

“…Disruption at this stage, specifically in the endothelium, was not lethal; these mice turned out to be relatively normal (Rode et al . ). However, when we studied freshly isolated endothelium from second‐order mesenteric resistance arteries we observed striking constitutive activity of endogenous channels which could be further enhanced by shear stress and which were totally dependent on Piezo1.…”

“…This channel activity was robust, maintained even in the sparse environment of the outside‐out patch (Rode et al . ). This suggested to us that the conditional Piezo1 knockout mice should have a phenotype.…”

“…This closer inspection led us to find that Piezo1 channels were opposing the component of the response attributed to endothelium‐dependent hyperpolarization (EDH) (Garland & Dora, ), consistent with constitutively active Piezo1 channels acting as an ‘anti‐EDH’ (Rode et al . ).…”

“…Summary of the hypothesis for how Piezo1 channels act as sensors of exercise to redistribute blood flow and enhance whole body physical performance (Rode et al . ).

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