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The mechanosensory channel PIEZO1 functions upstream of angiopoietin/TIE/FOXO1 signaling in lymphatic development
Jing Du, … , Jing Jin, Susan E. Quaggin
Jing Du, … , Jing Jin, Susan E. Quaggin
Published May 15, 2024
Citation Information: J Clin Invest. 2024;134(10):e176577. https://doi.org/10.1172/JCI176577.
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Research Article Development Vascular biology Article has an altmetric score of 43

The mechanosensory channel PIEZO1 functions upstream of angiopoietin/TIE/FOXO1 signaling in lymphatic development

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Abstract

Lymphedema is a debilitating disease with no effective cure and affects an estimated 250 million individuals worldwide. Prior studies have identified mutations in piezo-type mechanosensitive ion channel component 1 (PIEZO1), angiopoietin 2 (ANGPT2), and tyrosine kinase with Ig-like and EGF-like domains 1 (TIE1) in patients with primary lymphedema. Here, we identified crosstalk between these molecules and showed that activation of the mechanosensory channel PIEZO1 in lymphatic endothelial cells (LECs) caused rapid exocytosis of the TIE ligand ANGPT2, ectodomain shedding of TIE1 by disintegrin and metalloproteinase domain–containing protein 17 (ADAM17), and increased TIE/PI3K/AKT signaling, followed by nuclear export of the transcription factor FOXO1. These data establish a functional network between lymphedema-associated genes and provide what we believe to be the first molecular mechanism bridging channel function with vascular signaling and intracellular events culminating in transcriptional regulation of genes expressed in LECs. Our study provides insights into the regulation of lymphatic function and molecular pathways involved in human disease.

Authors

Jing Du, Pan Liu, Yalu Zhou, Sol Misener, Isha Sharma, Phoebe Leeaw, Benjamin R. Thomson, Jing Jin, Susan E. Quaggin

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Figure 4

TIE signaling partially mediates AKT/FOXO1 activation triggered by PIEZO1 signaling.

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TIE signaling partially mediates AKT/FOXO1 activation triggered by PIEZO...
(A) HDLECs were transfected with siCtr, siTIE1, siTIE2, or siTIE1/siTIE2 for 48 hours and then exposed to either vehicle or 250 nM Yoda1 for 30 minutes. After fixation, cells were stained for FOXO1. This experiment was carried out concurrently with the one depicted in Figure 3C. The samples used in the siCtr plus DMSO and siCtr plus Yoda1 groups were identical to those in Figure 3C. Scale bar: 50 μm. (B) Quantification of cells exhibiting nuclear FOXO1 staining. This experiment was repeated 3 times. (C) HDLECs were transfected with the specified siRNAs and treated with vehicle or Yoda1 as described above. Cell lysates were subjected to Western blot analysis to assess AKT phosphorylation. TIE2 was isolated from cell lysates via immunoprecipitation and subsequently analyzed by Western blotting to evaluate its phosphorylation status. Each band represents a biological replicate sample (n = 3). (D) qPCR analysis of HDLECs transfected with siCtr or siTIE1 and subsequently treated with Yoda1 (250 nM, 24 hours) or vehicle. Expression levels of TIE1, FOXC2, GATA2, GJA4, and ITGA9 genes were measured. Data are expressed as the mean ± SD. *P < 0.05, **P < 0.01, and ***P < 0.001, by 2-way ANOVA followed by Tukey’s multiple-comparison test (B and C) and 2-tailed, unpaired Student’s t test (D).

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

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