title: Piezo1 integration of vascular architecture with physiological force.
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.
authors.affiliation: School of Medicine and Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: School of Medicine and Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: Bing
authors.initials: B
authors.lastname: Hou
authors.affiliation: School of Medicine and Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: Sarka
authors.initials: S
authors.lastname: Tumova
authors.affiliation: School of Pharmacy, Aichi-Gakuin University, 1-100 Kusumoto, Chikusa, Nagoya 464-8650, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Muraki
authors.affiliation: School of Medicine and Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: Alexander
authors.initials: A
authors.lastname: Bruns
authors.affiliation: School of Medicine and Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: Ludlow
authors.affiliation: School of Medicine and Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: Alicia
authors.initials: A
authors.lastname: Sedo
authors.affiliation: School of Medicine and Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Hyman
authors.affiliation: School of Medicine and Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: Lynn
authors.initials: L
authors.lastname: McKeown
authors.affiliation: School of Medicine and Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, LS2 9JT, UK.|Department of Hepatobiliary and Transplant Surgery, St. James's University Hospital, Leeds, UK.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Young
authors.affiliation: School of Medicine and Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: Nadira Y
authors.initials: NY
authors.lastname: Yuldasheva
authors.affiliation: School of Medicine and Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: Yasser
authors.initials: Y
authors.lastname: Majeed
authors.affiliation: School of Medicine and Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Wilson
authors.affiliation: School of Medicine and Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: Baptiste
authors.initials: B
authors.lastname: Rode
authors.affiliation: School of Medicine and Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Bailey
authors.affiliation: Cardiovascular Science, University of Sheffield, Sheffield, S10 2RX, UK.
authors.forename: Hyejeong R
authors.initials: HR
authors.lastname: Kim
authors.affiliation: School of Medicine and Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: Zhaojun
authors.initials: Z
authors.lastname: Fu
authors.affiliation: School of Medicine and Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: Deborah Al
authors.initials: DA
authors.lastname: Carter
authors.affiliation: School of Medicine and Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: Jan
authors.initials: J
authors.lastname: Bilton
authors.affiliation: School of Medicine and Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Imrie
authors.affiliation: Dundee Cell Products Ltd, James Lindsay Place, Dundee, DD1 5JJ, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Ajuh
authors.affiliation: School of Medicine and Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: T Neil
authors.initials: TN
authors.lastname: Dear
authors.affiliation: School of Medicine and Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Cubbon
authors.affiliation: School of Medicine and Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Kearney
authors.affiliation: Department of Hepatobiliary and Transplant Surgery, St. James's University Hospital, Leeds, UK.
authors.forename: Raj K
authors.initials: RK
authors.lastname: Prasad
authors.affiliation: Cardiovascular Science, University of Sheffield, Sheffield, S10 2RX, UK.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Evans
authors.affiliation: School of Medicine and Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: Justin Fx
authors.initials: JF
authors.lastname: Ainscough
authors.affiliation: School of Medicine and Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Beech
mesh_terms: D000818:Animals; D004622:Embryo, Mammalian / Q000098:blood supply / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology* / Q000502:physiology*; D005260:Female; D017276:Friction; D018056:Hemorheology; D007473:Ion Channels / Q000378:metabolism*; D008297:Male; D051379:Mice; D013314:Stress, Mechanical
chemical_list: D007473:Ion Channels; C552920:Piezo1 protein, mouse