ZEB1 Modifies VE-Cadherin Signaling in Lymphatic Endothelial Cells

Authors

• Nada S Ahmed
• Joseph L Horder
• Charles T Cresswell
• Poppy E Harris
• Amy P Lynch
• Zarah B Tabrizi
• Kathryn R Green
• James H Hallwood
• Anton C Smith
• Michael A Portelli
• Alexander J Fezovich
• Christos Spanos
• David S Gardner
• Alan McIntyre
• Sarah J Storr
• Daniel G Booth
• David O Bates
• Andrew V Benest

Language

English

Publication Date

7-1-2026

Journal

Microcirculation

DOI

10.1111/micc.70076

PMID

42348369

PMCID

PMC13297878

PubMedCentral® Posted Date

6-25-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Objective: Zinc finger E-box-binding homeobox 1 (ZEB1) is a transcription factor primarily known for its regulatory roles in epithelial-to-mesenchymal transition (EMT) and cell fate determination. Recent studies suggest that endothelial ZEB1 signaling promotes blood vessel growth and reduces junctional integrity, although the underlying mechanisms remain unclear. Notably, the role of ZEB1 in the lymphatic vasculature is unknown, and the regulation of lymphatic integrity by VE-cadherin remains poorly defined.

Methods: Here, using an integrated proteomic and transcriptomic approach, we identify ZEB1-dependent signaling pathways associated with cell-cell junction reorganization in lymphatic endothelial cells (LECs).

Results: Loss of ZEB1 reduced VE-cadherin phosphorylation at pY731 and pY685 and was accompanied by decreased monolayer resistance and impedance, together with increased leukocyte transendothelial migration. ZEB1 knockdown also reduced YES tyrosine kinase expression and altered YAP1 expression and junctional localisation, changes that were associated with reduced VE-cadherin phosphorylation. Silencing YAP1 in HDLECs similarly reduced VE-cadherin phosphorylation and impaired barrier integrity, recapitulating aspects of the phenotype observed following ZEB1 knockdown.

Conclusions: Collectively, these findings suggest that ZEB1 contributes to lymphatic endothelial barrier maintenance in association with altered YAP1 and YES signaling.

Keywords

Cadherins, Zinc Finger E-box-Binding Homeobox 1, Cadherin 5, Antigens, CD, Signal Transduction, Endothelial Cells, Humans, Phosphorylation, Animals, YAP-Signaling Proteins

Published Open-Access

yes

Recommended Citation

Ahmed, Nada S; Horder, Joseph L; Cresswell, Charles T; et al., "ZEB1 Modifies VE-Cadherin Signaling in Lymphatic Endothelial Cells" (2026). Faculty, Staff and Students Publications. 8529.
https://digitalcommons.library.tmc.edu/baylor_docs/8529