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.
| Original language | English (US) |
|---|---|
| Article number | e176577 |
| Journal | Journal of Clinical Investigation |
| Volume | 134 |
| Issue number | 10 |
| DOIs | |
| State | Published - May 15 2024 |
Funding
This work was supported by the NIH grants RO1EY025799-05 and NIHP30DK114857 (to SEQ); NIH grant R01 EY032609 and a Brightfocus Foundation New Investigator Grant in Macular Degeneration Research (M2021018N, to BRT); the Northwestern University Transgenic and Targeted Mutagenesis Laboratory and the Center for Advanced Microscopy of the Feinberg School of Medicine, both supported by the National Cancer Institute (NCI) CCSG grant P30 CA60553 and NIH George M. O\u2019Brien kidney core grant P30 DK114857, awarded to the Section of Nephrology and Hypertension. We thank G. Oliver (Northwestern University Chicago, Illinois, USA) for critical review of our manuscript and helpful comments, Gou Young Koh (KAIST, Daejeon, Republic of Korea) for the angiopoeitin 2 antibody, and Young-Kwon Hong (Keck School of Medicine, USC, Los Angeles, California, USA) for sharing the Piezo1 conditional mouse strain. Authorship note: JD and P Liu are co\u2013first authors and contributed equally to this work. Conflict of interest: SEQ holds patents related to therapeutic targeting of the ANGPT/TEK pathway in ocular hypertension and glaucoma (patent nos. ZA202204983B, 9719135, WO2017190222A1,US20160000871A1, CA3168534A1, WO2021173999A1, US20230103583A1). SEQ also receives consulting fees from Astra-Zeneca, Janssen, the Lowy Medical Research Foundation, and Roche/Genentech; is a scientific advisor for AstraZeneca, Genentech/Roche, Merck, UNITY, Novartis, and Pfizer; and is on the board of directors of Abbvie. JJ, PL, and BRT have applied for a patent related to therapeutic targeting of the ANGPT/TEK pathway (see patent nos. listed above). BRT receives research funding from Bayer. Copyright: \u00A9 2024, Du et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. Submitted: October 19, 2023; Accepted: March 12, 2024; Published: May 15, 2024. Reference information: J Clin Invest. 2024;134(10):e176577. https://doi.org/10.1172/JCI176577.
ASJC Scopus subject areas
- General Medicine
