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PIEZO1 mediates mechanical reprogramming of neutrophils for proangiogenic specialization in the lung
Jin Wang, … , Bin Li, Jing Wang
Jin Wang, … , Bin Li, Jing Wang
Published June 2, 2025
Citation Information: J Clin Invest. 2025;135(11):e183796. https://doi.org/10.1172/JCI183796.
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Research Article Immunology Pulmonology Vascular biology

PIEZO1 mediates mechanical reprogramming of neutrophils for proangiogenic specialization in the lung

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Abstract

Neutrophils are the most abundant immune cells that constantly patrol or marginate inside vascular beds to support immune homeostasis. The extent to which neutrophils undergo reprogramming in response to the changes in vascular architecture and the resultant biological implications of such adaptations remain unclear. Here, we performed intravital imaging and transcriptional profiling to investigate neutrophil behavior across different tissues. Our findings revealed that neutrophils had significant deformability and spontaneous calcium signaling while navigating through the narrow pulmonary vessels. Pulmonary neutrophils exhibited unique transcriptional profiles and were specialized for proangiogenic functions. We found that the mechanosensitive ion channel Piezo-type mechanosensitive ion channel component 1 (PIEZO1) was essential for neutrophil reprogramming. Deletion of Piezo1 in neutrophils ablated the lung-specific proangiogenic transcriptional signature and impaired capillary angiogenesis in both physiological and pathological conditions. Collectively, these data show that mechanical adaptation of neutrophils within the pulmonary vasculature drives their reprogramming in the lungs and promotes pulmonary vascular homeostasis.

Authors

Jin Wang, Wenying Zhao, Wenjuan Bai, Dong Dong, Hui Wang, Xin Qi, Ajitha Thanabalasuriar, Youqiong Ye, Tian-le Xu, Hecheng Li, Paul Kubes, Bin Li, Jing Wang

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Figure 7

Intravascular activation of PIEZO1 induces VEGFA in neutrophils to sustain vascular homeostasis.

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Intravascular activation of PIEZO1 induces VEGFA in neutrophils to susta...
(A) Schematic of the experimental workflow. (B) Flow cytometric analysis of the percentage and number of CD31+Ki67+ cells and the total number of CD31+ cells in control and neutrophil-depleted lungs. n = 4 (neutrophil depletion); n = 6 (isotype control). (C) Schematic of the experimental workflow. (D) Volcano plot showing DEGs between control and neutrophil-depleted lungs. Transcripts significantly upregulated in either PMN-depleted or control lungs are colored in blue and red, respectively (log2 fold change ± 0.5 and adjusted P < 0.05). (E) GO enrichment analysis was performed on the DEGs. Blue indicates enrichment in lungs from neutrophil-depleted mice, while red indicates enrichment in lungs from control mice. (F) Intracellular VEGFA levels in neutrophils from the indicated tissues. n = 3–4 mice. (G) Percentage and absolute count of proliferating ECs in lungs from 3-week-old mice. n = 4 WT mice; n = 5 Piezo1-cKO mice. (H) Absolute count of total ECs in lung from 3-week-old mice. n = 4 WT mice; n = 5 Piezo1-cKO mice. (I) RVSP in normoxia (Nx) and hypoxia (Hx) for 3 weeks. n = 9 (Nx), n = 11 (Hx, WT); n = 12 (Hx, Piezo1-cKO). (J) Representative images and quantification of α-SMA–stained arterioles. Scale bars: 10 μm. n = 3. (K) Flow cytometric analysis of proliferating ECs in lung after 3 weeks of hypoxia. n = 4. Data in B and F–K are shown as the mean ± SEM. Statistical significance was determined by 1-way ANOVA with Tukey’s multiple-comparison test (I) and unpaired, 2-tailed Student’s t test (B, F, G, H, J, and K).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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