Endothelial Piezo1 sustains muscle capillary density and contributes to physical activity
Fiona Bartoli, … , Lee D. Roberts, David J. Beech
Fiona Bartoli, … , Lee D. Roberts, David J. Beech
Published January 13, 2022
Citation Information: J Clin Invest. 2022;132(5):e141775. https://doi.org/10.1172/JCI141775.
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Research Article Muscle biology Vascular biology

Endothelial Piezo1 sustains muscle capillary density and contributes to physical activity

Abstract

Piezo1 forms mechanically activated nonselective cation channels that contribute to endothelial response to fluid flow. Here we reveal an important role in the control of capillary density. Conditional endothelial cell–specific deletion of Piezo1 in adult mice depressed physical performance. Muscle microvascular endothelial cell apoptosis and capillary rarefaction were evident and sufficient to account for the effect on performance. There was selective upregulation of thrombospondin-2 (TSP2), an inducer of endothelial cell apoptosis, with no effect on TSP1, a related important player in muscle physiology. TSP2 was poorly expressed in muscle endothelial cells but robustly expressed in muscle pericytes, in which nitric oxide (NO) repressed the Tsp2 gene without an effect on Tsp1. In endothelial cells, Piezo1 was required for normal expression of endothelial NO synthase. The data suggest an endothelial cell–pericyte partnership of muscle in which endothelial Piezo1 senses blood flow to sustain capillary density and thereby maintain physical capability.

Authors

Fiona Bartoli, Marjolaine Debant, Eulashini Chuntharpursat-Bon, Elizabeth L. Evans, Katie E. Musialowski, Gregory Parsonage, Lara C. Morley, T. Simon Futers, Piruthivi Sukumar, T. Scott Bowen, Mark T. Kearney, Laeticia Lichtenstein, Lee D. Roberts, David J. Beech

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Figure 4

Protection against endothelial cell apoptosis.

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Protection against endothelial cell apoptosis. (A) Immunohistochemistry ...
(A) Immunohistochemistry for endothelial cells in capillaries (IB4, green), apoptotic cells (TUNEL, red), and nuclei (DAPI, blue) in gastrocnemius muscle sections. Merged images are shown on the right. Scale bars: 30 μm. Superimposed circles highlight an example of an apoptotic endothelial cell (IB4+TUNEL+DAPI+). (B) Quantification of apoptotic endothelial cell percentages in Ctrl and Piezo1ΔEC gastrocnemius muscle using images of the type shown in A. (C) Pearson’s correlation analysis of capillary density and percentage of apoptotic endothelial cells (r = –0.62, P = 0.014). (D) Pearson’s correlation analysis of apoptotic endothelial cell percentage and capillary regression (r = 0.75, P = 0.001). The black lines are the correlation fits. All data are for n = 7 to 8 mice per group (mean ± SD). (E) Quantitative PCR mRNA expression data for proapoptotic markers (Bax, Bak) and antiapoptotic markers (Bcl2, BclXL) in endothelial cells isolated from skeletal muscle of Ctrl (gray) and Piezo1ΔEC (blue) mice. (F) Quantitative PCR mRNA expression data for proapoptotic markers (Bax, Bak) and antiapoptotic markers (Bcl2, BclXL) in whole gastrocnemius muscle of Ctrl (gray) and Piezo1ΔEC (green) mice. RNA abundance was normalized to housekeeping gene expression and is presented as the fold-change relative to that in Ctrl mice. All data are for n = 5 to 6 mice per group for endothelial cells and n = 14 to 16 mice per group for whole muscle (mean ± SD). Superimposed dots are the individual underlying data values for each mouse. #P < 0.05, ##P < 0.01, ###P < 0.001 vs. Ctrl mice. Statistical significance was evaluated using Student’s t test, except in C and D where Pearson’s correlation was used.