The RhoGEF Trio regulates the formation of tensile linear endothelial junctions to improve barrier function
Year: 2025
Type: article
Abstract: The vascular endothelium serves as a selectively permeable barrier, tightly regulating transendothelial transport of small molecules, macromolecules, and immune cells. In the context of cardiovascular and inflammatory pathologies, the integrity of this barrier is often markedly compromised, contributing to tissue dysfunction, multi-organ failure, and, ultimately, mortality. Therapeutic strategies aimed at mitigating endothelial barrier dysfunction primarily focus on enhancing the stability of endothelial cell-cell junctions. However, the precise molecular mechanisms governing junctional stability remain incompletely understood. In this study, we demonstrate that the N-terminal domain of the Rho guanine nucleotide exchange factor Trio (TrioN) enhances endothelial junctional stability by promoting the formation of tensile F-actin bundles at intercellular junctions, thereby inducing a linear junctional architecture and packaging of junctional proteins. This structural reorganization leads to an increase in endothelial barrier function. The small GTPase Rap1 is responsible for junctional tension, as depletion of Rap1 results in reduced junctional tension, loss of linearity, and increased permeability. In vivo TrioN gain-of-function experiments reveal enhanced local mechanical tension and a concomitant improvement in vascular barrier integrity within atherosclerotic vein grafts in murine models. These findings position TrioN as a promising therapeutic target for the restoration and reinforcement of endothelial barrier function in vascular disease.
Source: Molecular Biology of the Cell
Institutions: Amsterdam UMC Location University of Amsterdam, Sanquin, Leiden University Medical Center, Amsterdam University Medical Centers, University of Amsterdam, The Netherlands Cancer Institute, Utrecht University, Brigham and Women's Hospital, Harvard University, Van Leeuwenhoek Centre for Advanced Microscopy
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7117165502