Endothelial Piezo1 sustains muscle capillary density and contributes to physical activity
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
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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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 6

In situ upregulation of TSP2 in pericytes.

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In situ upregulation of TSP2 in pericytes. (A and B) Relative mRNA abund...
(A and B) Relative mRNA abundance for (A) Tsp2 in isolated SkECs (gray) and pericytes (yellow) from WT mice, and (B) Tsp2 and Tsp1 in isolated pericytes from WT mice: untreated (yellow), treated with NO inhibitor (1 mM L-NMMA, light yellow), or with NO donor (300 μM GSNO, dark yellow/green) for 4 hours. mRNA abundance was determined by qRT-PCR, normalized to housekeeping gene expression, and is presented as fold-change relative to isolated SkECs (A) or untreated pericytes (B). (C) Immunohistochemistry for CD31 (green), NG2 (magenta), and TSP2 (yellow) in gastrocnemius muscle longitudinal sections. Merged images are shown on the right. TSP2 fluorescence intensity was measured in NG2+ regions (red). Scale bars: 15 μm. (D) Quantification of TSP2 fluorescence intensity in NG2+ regions corresponding to pericytes. (E) Schematic model of the mechanism. Data are for n = 4 mice per group (A and B) and n = 7 to 8 (C and D) (mean ± SD). Superimposed dots are the underlying data values for each mouse. #P < 0.05 vs. Ctrl mice; ***P < 0.001 vs. WT isolated SkECs; §P < 0.05 vs. untreated WT isolated pericytes. Statistical significance was evaluated using Student’s t test.