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

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Rode, Baptiste, Shi, Jian, Endesh, Naima, Drinkhill, Mark J., Webster, Peter J., Lotteau, Sabine J., Bailey, Marc A., Yuldasheva, Nadira Y., Ludlow, Melanie J., Cubbon, Richard M., Li, Jing, Futers, T. Simon, Morley, Lara, Gaunt, Hannah J., Marszalek, Katarzyna, Viswambharan, Hema, Cuthbertson, Kevin, Baxter, Paul D., Foster, Richard, Sukumar, Piruthivi, Weightman, Andrew, Calaghan, Sarah C., Wheatcroft, Stephen B., Kearney, Mark T., Beech, David J.·2017·Nature Communications
DOI 10.1038/s41467-017-00429-3PMC PMC5571199
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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 Ca 2+ 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.

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Fig. 1 Mice with disrupted endothelial Piezo1 are superficially normal. a Physical appearance of control and endothelial Piezo1-deleted (Piezo1ΔEC) mice. b Body weight and percentage change in body weight of control (n = 13) and Piezo1ΔEC (n = 14) mice before and 10–14 days after tamoxifen (TAM) treatment. c As percentages of total body weight, weights of heart, lung, kidney and liver in control (n = 13) and Piezo1ΔEC (n = 14) mice. d Histological examples of control (top row) and Piezo1ΔEC (bottom row) sections of aorta, heart, lung, kidney and liver stained with H&E. Scale bars 100 μm. e–g Serum concentrations of urea, K+ and Na+ in control (n = 7) and Piezo1ΔEC (n = 7) mice. h–m Ultrasound study of the heart h–j and aorta k–m of control (n = 5) and Piezo1ΔEC (n = 5) mice under anaesthesia. h Example of left ventricle images of control and Piezo1ΔEC at diastole and systole. The left ventricle chamber is circled with a white dashed line. Scale bar 1 mm. i, j Cardiac parameters measured by ultrasound. k Example of aorta images of control and Piezo1ΔEC at diastole and systole. The left ventricle chamber is circled with a white dashed line. Scale bar 1 mm. l Aorta anteroposterior diameter at systole. m Aortic distensibility. n Retinal vasculatures stained with isolectin (green) from control and Piezo1ΔEC mice. Entire retinas (full view) and close up views (zoom). o Quantification of retina distal artery diameter and capillary plexus area from control (n = 5) and Piezo1ΔEC (n = 4) mice. p Endothelial regeneration 5 days after femoral artery injury. Images of the arteries in which the blue colour shows Evans blue staining of areas which were not re-endothelialized after injury. Scale bars 0.5 mm. q Quantification of endothelial regeneration in control (n = 9) and Piezo1ΔEC (n = 7) mice. Independent data points are displayed with superimposed bars indicating mean ± s.e.m. Data sets are compared by t-test. No significant differences were detected
Fig. 1 Mice with disrupted endothelial Piezo1 are superficially normal. a Physical appearance of control and endothelial Piezo1-deleted (Piezo1ΔEC) mice. b Body weight and percentage change in body weight of control (n = 13) and Piezo1ΔEC (n = 14) mice before and 10–14 days after tamoxifen (TAM) treatment. c As percentages of total body weight, weights of heart, lung, kidney and liver in control (n = 13) and Piezo1ΔEC (n = 14) mice. d Histological examples of control (top row) and Piezo1ΔEC (bottom row) sections of aorta, heart, lung, kidney and liver stained with H&E. Scale bars 100 μm. e–g Serum concentrations of urea, K+ and Na+ in control (n = 7) and Piezo1ΔEC (n = 7) mice. h–m Ultrasound study of the heart h–j and aorta k–m of control (n = 5) and Piezo1ΔEC (n = 5) mice under anaesthesia. h Example of left ventricle images of control and Piezo1ΔEC at diastole and systole. The left ventricle chamber is circled with a white dashed line. Scale bar 1 mm. i, j Cardiac parameters measured by ultrasound. k Example of aorta images of control and Piezo1ΔEC at diastole and systole. The left ventricle chamber is circled with a white dashed line. Scale bar 1 mm. l Aorta anteroposterior diameter at systole. m Aortic distensibility. n Retinal vasculatures stained with isolectin (green) from control and Piezo1ΔEC mice. Entire retinas (full view) and close up views (zoom). o Quantification of retina distal artery diameter and capillary plexus area from control (n = 5) and Piezo1ΔEC (n = 4) mice. p Endothelial regeneration 5 days after femoral artery injury. Images of the arteries in which the blue colour shows Evans blue staining of areas which were not re-endothelialized after injury. Scale bars 0.5 mm. q Quantification of endothelial regeneration in control (n = 9) and Piezo1ΔEC (n = 7) mice. Independent data points are displayed with superimposed bars indicating mean ± s.e.m. Data sets are compared by t-test. No significant differences were detectedCC BY · PubMed Central
Fig. 2 Endothelial Piezo1 channels have an anti-EDH(F) effect. Isometric tension recordings from mouse second-order mesenteric artery. a Example recordings from control genotype artery before (+ EC) and after endothelium-denudation (−EC). Upward deflection is increasing tension. Phenylephrine (PE, 0.3 μM). Acetylcholine (ACh) and the nitric oxide donor amino-3-morpholinyl-1,2,3-oxadiazolium (SIN-1) were applied at increasing concentrations as indicated by the dots (0.01, 0.03, 0.1, 0.3 and 1 μM). b As for a but mean data (n = 14 mice). c, d As for a, b but Piezo1ΔEC mice (n = 10 mice). e Schematic illustration of the dichotomy Piezo1 presents for endothelial biology and vascular function. EC, endothelial cell. VSMC, vascular smooth muscle cell. eNOS, endothelial nitric oxide synthase. NO, nitric oxide. EDH(F), endothelium-derived hyperpolarization (factor). f Example recordings from control genotype artery before and after application of apamin (Apa, 0.5 μM) and charybdotoxin (Ch, 0.1 μM). Phenylephrine (PE, 0.3 μM). Acetylcholine (ACh) was applied at increasing concentrations as indicated by the dots (0.01, 0.03, 0.1, 0.3 and 1 μM). g As for f but mean data (n = 8 mice). h, i As for f, g but for Piezo1ΔEC mice (n = 6 mice). Averaged data are displayed as mean ± s.e.m. Data sets are compared by t-test. Statistical significance is indicated by *P < 0.05, **P < 0.01, ***P < 0.001
Fig. 2 Endothelial Piezo1 channels have an anti-EDH(F) effect. Isometric tension recordings from mouse second-order mesenteric artery. a Example recordings from control genotype artery before (+ EC) and after endothelium-denudation (−EC). Upward deflection is increasing tension. Phenylephrine (PE, 0.3 μM). Acetylcholine (ACh) and the nitric oxide donor amino-3-morpholinyl-1,2,3-oxadiazolium (SIN-1) were applied at increasing concentrations as indicated by the dots (0.01, 0.03, 0.1, 0.3 and 1 μM). b As for a but mean data (n = 14 mice). c, d As for a, b but Piezo1ΔEC mice (n = 10 mice). e Schematic illustration of the dichotomy Piezo1 presents for endothelial biology and vascular function. EC, endothelial cell. VSMC, vascular smooth muscle cell. eNOS, endothelial nitric oxide synthase. NO, nitric oxide. EDH(F), endothelium-derived hyperpolarization (factor). f Example recordings from control genotype artery before and after application of apamin (Apa, 0.5 μM) and charybdotoxin (Ch, 0.1 μM). Phenylephrine (PE, 0.3 μM). Acetylcholine (ACh) was applied at increasing concentrations as indicated by the dots (0.01, 0.03, 0.1, 0.3 and 1 μM). g As for f but mean data (n = 8 mice). h, i As for f, g but for Piezo1ΔEC mice (n = 6 mice). Averaged data are displayed as mean ± s.e.m. Data sets are compared by t-test. Statistical significance is indicated by *P < 0.05, **P < 0.01, ***P < 0.001CC BY · PubMed Central
Fig. 3 Importance for elevated blood pressure during whole body physical activity. Telemetry measurements of mean, systolic and diastolic blood pressures in conscious freely moving control (n = 6) and Piezo1ΔEC (n = 7) mice. Data were analysed when the mice were inactive during the day a and voluntarily active on a running wheel during the night b. Time zero is when the mouse was introduced to the running wheel cage. Measurements were not made during the first 2 days of acclimatization. Averaged data are displayed as mean ± s.e.m. Data sets are compared by t-test. Statistical significance is indicated by *P < 0.05, **P < 0.01, ***P < 0.001
Fig. 3 Importance for elevated blood pressure during whole body physical activity. Telemetry measurements of mean, systolic and diastolic blood pressures in conscious freely moving control (n = 6) and Piezo1ΔEC (n = 7) mice. Data were analysed when the mice were inactive during the day a and voluntarily active on a running wheel during the night b. Time zero is when the mouse was introduced to the running wheel cage. Measurements were not made during the first 2 days of acclimatization. Averaged data are displayed as mean ± s.e.m. Data sets are compared by t-test. Statistical significance is indicated by *P < 0.05, **P < 0.01, ***P < 0.001CC BY · PubMed Central
Fig. 4 Piezo1 channels are flow sensors in endothelium of mesenteric resistance artery. Data are for ionic current recordings from outside-out patches excised from freshly isolated endothelium of second-order mesenteric arteries. a Example recording at −70 mV. Two sections are expanded to clarify unitary current events (C: channel closed) (O: 1, 2 or 3 simultaneous channel openings). The patch was placed at the outlet of a capillary from which flowed ionic solution at 20 μl s−1. Gadolinium ion (Gd3+, 10 μM). b Mean unitary current amplitudes for channels activated by flow as in a (n = 10). c Mean channel activity (NPo: number × probability of opening) for experiments of the type exemplified in a for no flow and flow conditions and the two genotypes (Control and Piezo1ΔEC). Individual data points for each independent experiment are shown as symbols, superimposed on which are the mean ± s.e.m. values (n = 10 for each group). d Example original trace for a patch from Piezo1ΔEC endothelium exposed to 20 μl s−1 flow. Averaged data are displayed as mean ± s.e.m. Data sets are compared by t-test. Statistical significance is indicated by ***P < 0.001
Fig. 4 Piezo1 channels are flow sensors in endothelium of mesenteric resistance artery. Data are for ionic current recordings from outside-out patches excised from freshly isolated endothelium of second-order mesenteric arteries. a Example recording at −70 mV. Two sections are expanded to clarify unitary current events (C: channel closed) (O: 1, 2 or 3 simultaneous channel openings). The patch was placed at the outlet of a capillary from which flowed ionic solution at 20 μl s−1. Gadolinium ion (Gd3+, 10 μM). b Mean unitary current amplitudes for channels activated by flow as in a (n = 10). c Mean channel activity (NPo: number × probability of opening) for experiments of the type exemplified in a for no flow and flow conditions and the two genotypes (Control and Piezo1ΔEC). Individual data points for each independent experiment are shown as symbols, superimposed on which are the mean ± s.e.m. values (n = 10 for each group). d Example original trace for a patch from Piezo1ΔEC endothelium exposed to 20 μl s−1 flow. Averaged data are displayed as mean ± s.e.m. Data sets are compared by t-test. Statistical significance is indicated by ***P < 0.001CC BY · PubMed Central
Fig. 5 Ca2+ channel activation in vascular smooth muscle cells. a, b Membrane potential measurements from freshly isolated endothelium of second-order mesenteric arteries. a Example traces from the control and Piezo1ΔEC genotypes in the absence of Gd3+ and the control genotype in the presence of 10 μM Gd3+. Endothelium was exposed to flow at 20 μl s−1. b As for a but individual data points for the three independent experiments shown as symbols. Control genotype: no flow −46.3 ± 2.4 mV vs flow −38.4 ± 2.1 mV (***). Control genotype in Gd3+: no flow −60.1 ± 3.1 mV vs flow −56.5 ± 3.3 mV (***). Piezo1ΔEC genotype: no flow −59.5 ± 2.3 mV vs flow −60.7 ± 2.5 mV (*). c As for a, b but a separate series of experiments in which endothelium was exposed to increasing flow in the absence of Gd3+ for control (n = 10) and Piezo1ΔEC (n = 6) genotypes. d Example current recordings from vascular smooth muscle cells (VSMC) freshly isolated from second-order mesenteric artery. Square-step depolarizations were applied at the time of the arrow from a holding voltage of −80 mV to the test voltage indicated. Linear leak and capacitance currents were subtracted. e Mean data for peak VSMC inward currents of the type exemplified in d (current, n = 8). Superimposed in grey are endothelial shear stress values calculated from the control genotype data in c. Membrane potential for the highest shear stress was obtained by extrapolation based on a least-squares fit of the Hill equation. Averaged data are displayed as mean ± s.e.m. Data sets are compared by t-test. Statistical significance is indicated by ***P < 0.001
Fig. 5 Ca2+ channel activation in vascular smooth muscle cells. a, b Membrane potential measurements from freshly isolated endothelium of second-order mesenteric arteries. a Example traces from the control and Piezo1ΔEC genotypes in the absence of Gd3+ and the control genotype in the presence of 10 μM Gd3+. Endothelium was exposed to flow at 20 μl s−1. b As for a but individual data points for the three independent experiments shown as symbols. Control genotype: no flow −46.3 ± 2.4 mV vs flow −38.4 ± 2.1 mV (***). Control genotype in Gd3+: no flow −60.1 ± 3.1 mV vs flow −56.5 ± 3.3 mV (***). Piezo1ΔEC genotype: no flow −59.5 ± 2.3 mV vs flow −60.7 ± 2.5 mV (*). c As for a, b but a separate series of experiments in which endothelium was exposed to increasing flow in the absence of Gd3+ for control (n = 10) and Piezo1ΔEC (n = 6) genotypes. d Example current recordings from vascular smooth muscle cells (VSMC) freshly isolated from second-order mesenteric artery. Square-step depolarizations were applied at the time of the arrow from a holding voltage of −80 mV to the test voltage indicated. Linear leak and capacitance currents were subtracted. e Mean data for peak VSMC inward currents of the type exemplified in d (current, n = 8). Superimposed in grey are endothelial shear stress values calculated from the control genotype data in c. Membrane potential for the highest shear stress was obtained by extrapolation based on a least-squares fit of the Hill equation. Averaged data are displayed as mean ± s.e.m. Data sets are compared by t-test. Statistical significance is indicated by ***P < 0.001CC BY · PubMed Central
Fig. 6 Flow-evoked vasoconstriction in mesenteric artery. Isobaric external diameter recordings from second-order mesenteric artery. a Example images of a cannulated artery before and after luminal pressure difference (ΔP) and then after 10 μM nicardipine was added to the recording chamber. Control genotype mouse. Scale bar, 200 μm. b Example diameter recording for a control genotype mouse during incremental increases in ΔP as indicated by the black dots (20, 40, 60, 70, 80, 90 and 100 mm Hg). Nicardipine (Nic, 10 μM), phenylephrine (PE, 1 μM) and acetylcholine (ACh, 10 μM) were applied as indicated. The first arrow indicates addition of 100 μM N(ω)-nitro-L-arginine methyl ester (L-NAME) to the recording chamber and the second arrow multiple washes of the chamber to remove nicardipine and L-NAME. c Mean data for the type of experiment shown in b presented as the constriction to ΔP as a percentage of the PE response (9 arteries from n = 6 mice). Nicardipine significantly (***) reduced the 100 mm Hg ΔP response to 30.7 ± 3.9% (n = 6 mice). d, e The same as for b, c but using Piezo1ΔEC genotype mice (8 arteries from n = 3 mice). Averaged data are displayed as mean ± s.e.m. Data sets are compared by t-test. Statistical significance is indicated by **P < 0.01, ***P < 0.001
Fig. 6 Flow-evoked vasoconstriction in mesenteric artery. Isobaric external diameter recordings from second-order mesenteric artery. a Example images of a cannulated artery before and after luminal pressure difference (ΔP) and then after 10 μM nicardipine was added to the recording chamber. Control genotype mouse. Scale bar, 200 μm. b Example diameter recording for a control genotype mouse during incremental increases in ΔP as indicated by the black dots (20, 40, 60, 70, 80, 90 and 100 mm Hg). Nicardipine (Nic, 10 μM), phenylephrine (PE, 1 μM) and acetylcholine (ACh, 10 μM) were applied as indicated. The first arrow indicates addition of 100 μM N(ω)-nitro-L-arginine methyl ester (L-NAME) to the recording chamber and the second arrow multiple washes of the chamber to remove nicardipine and L-NAME. c Mean data for the type of experiment shown in b presented as the constriction to ΔP as a percentage of the PE response (9 arteries from n = 6 mice). Nicardipine significantly (***) reduced the 100 mm Hg ΔP response to 30.7 ± 3.9% (n = 6 mice). d, e The same as for b, c but using Piezo1ΔEC genotype mice (8 arteries from n = 3 mice). Averaged data are displayed as mean ± s.e.m. Data sets are compared by t-test. Statistical significance is indicated by **P < 0.01, ***P < 0.001CC BY · PubMed Central
Fig. 7 Physical performance depends on endothelial Piezo1. Voluntary running wheel data for control and Piezo1ΔEC genotypes from the dark cycle (active period) showing distance run on the wheel a, percentage time for which mice were active on the wheel b and the number of active bouts of exercise c (n = 12 mice per group). d As for c but summary analysis for all bouts of activity. e For the same mice analysed in a–d, changes in body weight during the 12 days prior to and 7 days after access to the wheel (n = 12 mice per group). Averaged data are displayed as mean ± s.e.m. Data sets are compared by t-test. Statistical significance is indicated by *P < 0.05
Fig. 7 Physical performance depends on endothelial Piezo1. Voluntary running wheel data for control and Piezo1ΔEC genotypes from the dark cycle (active period) showing distance run on the wheel a, percentage time for which mice were active on the wheel b and the number of active bouts of exercise c (n = 12 mice per group). d As for c but summary analysis for all bouts of activity. e For the same mice analysed in a–d, changes in body weight during the 12 days prior to and 7 days after access to the wheel (n = 12 mice per group). Averaged data are displayed as mean ± s.e.m. Data sets are compared by t-test. Statistical significance is indicated by *P < 0.05CC BY · PubMed Central
Fig. 8 Contribution of endothelial Piezo1 is vascular bed specific. Isometric tension recordings from mouse saphenous or carotid artery. a Example recordings from control genotype saphenous artery before and after application of apamin (Apa, 0.5 μM) and charybdotoxin (Ch, 0.1 μM). Phenylephrine (PE, 0.3 μM). Acetylcholine (ACh) was applied at increasing concentrations as indicated by the dots (0.01, 0.03, 0.1, 0.3 and 1 μM). b As for a but mean data (n = 5 mice). c, d As for a, b but for Piezo1ΔEC mice (n = 5 mice). e–h As for a–d but carotid artery (n = 5 control mice, n = 5 Piezo1ΔEC mice). Averaged data are displayed as mean ± s.e.m. Data sets are compared by t-test. Statistical significance is indicated by *P < 0.05, **P < 0.01
Fig. 8 Contribution of endothelial Piezo1 is vascular bed specific. Isometric tension recordings from mouse saphenous or carotid artery. a Example recordings from control genotype saphenous artery before and after application of apamin (Apa, 0.5 μM) and charybdotoxin (Ch, 0.1 μM). Phenylephrine (PE, 0.3 μM). Acetylcholine (ACh) was applied at increasing concentrations as indicated by the dots (0.01, 0.03, 0.1, 0.3 and 1 μM). b As for a but mean data (n = 5 mice). c, d As for a, b but for Piezo1ΔEC mice (n = 5 mice). e–h As for a–d but carotid artery (n = 5 control mice, n = 5 Piezo1ΔEC mice). Averaged data are displayed as mean ± s.e.m. Data sets are compared by t-test. Statistical significance is indicated by *P < 0.05, **P < 0.01CC BY · PubMed Central

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Authors
Rode, B., Shi, J., Endesh, N., Drinkhill, M. J., Webster, P. J., Lotteau, S. J., Bailey, M. A., Yuldasheva, N. Y., Ludlow, M. J., Cubbon, R. M., Li, J., Futers, T. S., Morley, L., Gaunt, H. J., Marszalek, K., Viswambharan, H., Cuthbertson, K., Baxter, P. D., Foster, R., Sukumar, P., Weightman, A., Calaghan, S. C., Wheatcroft, S. B., Kearney, M. T., & Beech, D. J.
Affiliations
  • University of Leeds (GB)
  • University of Manchester (GB)
Corresponding author
Beech, David J.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2017-08-24
Volume
8
Issue
1
Pages
350-350
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-017-00429-3
PMC
PMC5571199
OpenAlex
W2747918806
Cited by
305
References
32
Citations by year
2026: 37 · 2025: 31 · 2024: 44 · 2023: 32 · 2022: 49 · 2021: 40 · 2020: 18 · 2019: 31 · 2018: 20 · 2017: 3
FWCI
12.32
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Research Explorer (The University of Manchester) (submittedVersion, cc-by)
Funders
  • Wellcome Trust (110044/Z/15/Z)
  • National Institute for Health and Care Research (ACF-2014-02-003)
  • British Heart Foundation (RG/15/7/31521, PG/12/88/29951, FS/12/80/29821, FS/14/22/30734, FS/17/2/32559)
  • Medical Research Council (MR/L019051/1, MR/P002099/1)
Topics
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
  • Health Sciences › Medicine › Physiology (medical) › Erythrocyte Function and Pathophysiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
Keywords
Piezo1, mechanical force sensing, endothelium-dependent relaxation, mesenteric resistance arteries, blood pressure, vasoconstriction, voltage-gated calcium channels, vascular smooth muscle, physical performance, weight loss, cardiovascular homeostasis
MeSH terms
Animals, Blood Pressure, Cells, Cultured, Homeostasis, Humans, Ion Channels, Male, Physical Conditioning, Animal, Vasoconstriction, Patch-Clamp Techniques, Calcium Signaling, Myocytes, Smooth Muscle, Endothelial Cells, Mice, HEK293 Cells

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