Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
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

  • Text
  • PDF
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

×

Figure 6

PIEZO1 activation promotes ADAM17-mediated TIE1 shedding in HDLECs.

Options: View larger image (or click on image) Download as PowerPoint
PIEZO1 activation promotes ADAM17-mediated TIE1 shedding in HDLECs.
(A) ...
(A) Following a 30-minute treatment with Yoda1, HDLECs displayed a reduced distribution of TIE1 at cell-cell junctions (indicated by arrows), as observed in TIE1 and tight-junction protein 1 (ZO-1) immunostaining. Scale bar: 20 μm. (B) Yoda1-treated HDLECs exhibited increased TIE1 shedding, as confirmed by Western blot analysis (left panel: cell lysate protein samples; right panel: protein samples obtained from TCA precipitation of the culture medium). Each band represents a biological replicate sample (n = 3). (C) HDLECs treated with either siCtr or siADAM17 were stimulated with Yoda1 or vehicle control, followed by staining for TIE1 and ZO-1. Arrows highlight the areas at cell-cell junctions where TIE1 shedding occurred. Scale bars: 50 μm. (D) TIE1 shedding was assessed by Western blot analysis using medium samples subjected to TCA precipitation from siCtr-, siADAM17-, or siADAM10-treated HDLECs after vehicle or Yoda1 treatment. sTIE1, soluble TIE1. Each band represents a biological replicate sample (n = 3). Data are expressed as the mean ± SD. *P < 0.05, **P < 0.01, and ***P < 0.001, by 2-tailed, unpaired Student’s t test (B) or 2-way ANOVA followed by Tukey’s multiple-comparison test (D).

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

Sign up for email alerts

Picked up by 4 news outlets
Blogged by 1
Posted by 25 X users
On 1 Facebook pages
10 readers on Mendeley
See more details