Piezo1 integration of vascular architecture with physiological force

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Abstract

The mechanisms by which physical forces regulate endothelial cells to determine the complexities of vascular structure and function are enigmatic ^{1-
5}. Studies of sensory neurons have suggested Piezo proteins as subunits of Ca ²⁺-permeable non-selective cationic channels for detection of noxious mechanical impact ^{6-
8}. 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. 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 was protease activity and spatial organization of endothelial cells to the polarity of the applied force. The data suggest Piezo1 channels as pivotal integrators in vascular biology.

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Most cited references 26

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Piezos are pore-forming subunits of mechanically activated channels

Bertrand Coste, Bailong Xiao, José S. Santos … (2012)

Mechanotransduction plays a crucial role in physiology. Biological processes including sensing touch and sound waves require yet unidentified cation channels that detect pressure. Mouse piezo1 (mpiezo1) and mpiezo2 induce mechanically activated cationic currents in cells; however, it is unknown if piezos are pore-forming ion channels or modulate ion channels. We show that Drosophila piezo (dpiezo) also induces mechanically activated currents in cells, but through channels with remarkably distinct pore properties including sensitivity to the pore blocker ruthenium red and single channel conductances. mpiezo1 assembles as a ~1.2 million-Dalton tetramer, with no evidence of other proteins in this complex. Finally, purified mpiezo1 reconstituted into asymmetric lipid bilayers and liposomes forms ruthenium red-sensitive ion channels. These data demonstrate that piezos are an evolutionarily conserved ion channel family involved in mechanotransduction.

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Experimental investigation of collagen waviness and orientation in the arterial adventitia using confocal laser scanning microscopy.

R Rezakhaniha, A Agianniotis, J T C Schrauwen … (2012)

Mechanical properties of the adventitia are largely determined by the organization of collagen fibers. Measurements on the waviness and orientation of collagen, particularly at the zero-stress state, are necessary to relate the structural organization of collagen to the mechanical response of the adventitia. Using the fluorescence collagen marker CNA38-OG488 and confocal laser scanning microscopy, we imaged collagen fibers in the adventitia of rabbit common carotid arteries ex vivo. The arteries were cut open along their longitudinal axes to get the zero-stress state. We used semi-manual and automatic techniques to measure parameters related to the waviness and orientation of fibers. Our results showed that the straightness parameter (defined as the ratio between the distances of endpoints of a fiber to its length) was distributed with a beta distribution (mean value 0.72, variance 0.028) and did not depend on the mean angle orientation of fibers. Local angular density distributions revealed four axially symmetric families of fibers with mean directions of 0°, 90°, 43° and -43°, with respect to the axial direction of the artery, and corresponding circular standard deviations of 40°, 47°, 37° and 37°. The distribution of local orientations was shifted to the circumferential direction when measured in arteries at the zero-load state (intact), as compared to arteries at the zero-stress state (cut-open). Information on collagen fiber waviness and orientation, such as obtained in this study, could be used to develop structural models of the adventitia, providing better means for analyzing and understanding the mechanical properties of vascular wall.

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The mechanosensitive ion channel Piezo1 is inhibited by the peptide GsMTx4.

Chilman Bae, P Gottlieb, Frederick Sachs (2011)

Cells can respond to mechanical stress by gating mechanosensitive ion channels (MSCs). The cloning of Piezo1, a eukaryotic cation selective MSC, defines a new system for studying mechanical transduction at the cellular level. Because Piezo1 has electrophysiological properties similar to those of endogenous cationic MSCs that are selectively inhibited by the peptide GsMTx4, we tested whether the peptide targets Piezo1 activity. Extracellular GsMTx4 at micromolar concentrations reversibly inhibited ∼80% of the mechanically induced current of outside-out patches from transfected HEK293 cells. The inhibition was voltage insensitive, and as seen with endogenous MSCs, the mirror image d enantiomer inhibited like the l. The rate constants for binding and unbinding based on Piezo1 current kinetics provided association and dissociation rates of 7.0 × 10(5) M(-1) s(-1) and 0.11 s(-1), respectively, and a K(D) of ∼155 nM, similar to values previously reported for endogenous MSCs. Consistent with predicted gating modifier behavior, GsMTx4 produced an ∼30 mmHg rightward shift in the pressure-gating curve and was active on closed channels. In contrast, streptomycin, a nonspecific inhibitor of cationic MSCs, showed the use-dependent inhibition characteristic of open channel block. The peptide did not block currents of the mechanical channel TREK-1 on outside-out patches. Whole-cell Piezo1 currents were also reversibly inhibited by GsMTx4, and although the off rate was nearly identical to that of outside-out patches, differences were observed for the on rate. The ability of GsMTx4 to target the mechanosensitivity of Piezo1 supports the use of this channel in high-throughput screens for pharmacological agents and diagnostic assays. © 2011 American Chemical Society

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Author and article information

Journal

Journal ID (nlm-journal-id): 0410462

Journal ID (pubmed-jr-id): 6011

Journal ID (nlm-ta): Nature

Journal ID (iso-abbrev): Nature

Title: Nature

ISSN (Print): 0028-0836

ISSN (Electronic): 1476-4687

Publication date Nihms-submitted: 5 August 2014

Publication date (Electronic): 10 August 2014

Publication date (Print): 13 November 2014

Publication date PMC-release: 13 May 2015

Volume: 515

Issue: 7526

Pages: 279-282

Affiliations

[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.

Author notes

Author ContributionsL JL initiated the experimental studies of Piezo1 and was the primary contributor to experiments on endothelial cell tube formation, Piezo1 gene-modified mice, and Piezo1 over-expression. BH initiated the experimental studies of shear stress and was the primary contributor to experiments on shear stress-evoked Ca ²⁺ responses, Piezo1 redistribution, and Piezo1-dependence of endothelial cell alignment. JL and BH addressed the calpain hypothesis. ST initiated the proteomic experiments and nitric oxide studies. KM performed patch-clamp experiments. AS, RSY, NYY, LM, YM, LAW, BR, AB, MJL, AJH, DAL, JB, PA and RMC also contributed to experiments or prepared cells, mice or reagents. JL, BH, ST, KM, HI, ZF and AJH analyzed data, interpreted data and developed methods. RKP provided essential material. JL, BH, ST, KM, HRK, MTK, MAB, TND, PCE and JFXA provided intellectual input. All authors commented on the manuscript. DJB initiated the project, generated research funds and ideas, led and coordinated the project, interpreted data, and wrote the paper.

[* ]Author for correspondence: Prof David J Beech, School of Medicine, Garstang Building, Mount Preston Street, University of Leeds, Leeds, LS2 9JT, England, UK; d.j.beech@ 123456leeds.ac.uk ; Tel +44 (0) 113 34 34323

Article

Manuscript ID: EMS59764

DOI: 10.1038/nature13701

PMC ID: 4230887

PubMed ID: 25119035

SO-VID: 92e260bb-3da4-4bbb-8674-349128e1e29d

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Piezo1 integration of vascular architecture with physiological force

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Vascular Biology

Most cited references 26

Piezos are pore-forming subunits of mechanically activated channels

Experimental investigation of collagen waviness and orientation in the arterial adventitia using confocal laser scanning microscopy.

The mechanosensitive ion channel Piezo1 is inhibited by the peptide GsMTx4.

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