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Nature. 2014 Nov 13;515(7526):279-282. doi: 10.1038/nature13701. Epub 2014 Aug 10.

Piezo1 integration of vascular architecture with physiological force.

Author information

1
School of Medicine and Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, LS2 9JT, UK.
2
School of Pharmacy, Aichi-Gakuin University, 1-100 Kusumoto, Chikusa, Nagoya 464-8650, Japan.
3
Department of Hepatobiliary and Transplant Surgery, St. James's University Hospital, Leeds, UK.
4
Cardiovascular Science, University of Sheffield, Sheffield, S10 2RX, UK.
5
Dundee Cell Products Ltd, James Lindsay Place, Dundee, DD1 5JJ, UK.
#
Contributed equally

Abstract

The mechanisms by which physical forces regulate endothelial cells to determine the complexities of vascular structure and function are enigmatic. Studies of sensory neurons have suggested Piezo proteins as subunits of Ca(2+)-permeable non-selective cationic channels for detection of noxious mechanical impact. Here we show Piezo1 (Fam38a) channels as sensors of frictional force (shear stress) and determinants of vascular structure in both development and adult physiology. Global or endothelial-specific disruption of mouse Piezo1 profoundly disturbed the developing vasculature and was embryonic lethal within days of the heart beating. Haploinsufficiency was not lethal but endothelial abnormality was detected in mature vessels. The importance of Piezo1 channels as sensors of blood flow was shown by Piezo1 dependence of shear-stress-evoked ionic current and calcium influx in endothelial cells and the ability of exogenous Piezo1 to confer sensitivity to shear stress on otherwise resistant cells. Downstream of this calcium influx there was protease activation and spatial reorganization of endothelial cells to the polarity of the applied force. The data suggest that Piezo1 channels function as pivotal integrators in vascular biology.

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PMID:
25119035
PMCID:
PMC4230887
DOI:
10.1038/nature13701
[Indexed for MEDLINE]
Free PMC Article

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