Endothelial Junction Regulation and Vascular Integrity

The vascular endothelium forms a dynamic barrier that regulates fluid, solute and leukocyte passage while withstanding shear stress. Integrity is governed by two principal junctional complexes: adherens junctions, centred on vascular endothelial cadherin (VE-cadherin) linked to the actomyosin cytoskeleton, and tight junctions composed of claudins, occludin and junctional adhesion molecules. Complementary cell–matrix adhesions mediated by integrins provide anchorage and mechanotransduction. Barrier stability depends on finely tuned signalling through small GTPases, kinases, phosphatases and ubiquitin E3 ligases, which control junction assembly, remodelling and protein turnover. Dysregulation of these pathways underlies pathological vascular leakage in conditions such as acute respiratory distress, inflammation and tumour angiogenesis. Recent discoveries into targeted protein degradation, actin-driven junctional structures and cross-talk between cell–cell and cell–matrix adhesions have unveiled novel therapeutic strategies to preserve or restore endothelial barrier function.

Research from Nature Portfolio

A specific E3 ubiquitin ligase has been shown to target VE-cadherin for degradation in response to inflammatory cues, driving rapid disassembly of adherens junctions and promoting vascular leak. Endothelial-specific deletion of this ligase stabilises VE-cadherin levels, preserves barrier function in endotoxaemia models and highlights a promising anti-inflammatory approach.

Histamine engagement of G protein–coupled receptors activates RhoA and downstream ROCK-dependent actomyosin contraction, leading to adherens junction disruption and fluid extravasation. Endothelial deletion of RhoA or pharmacological ROCK inhibition effectively prevents histamine-induced leakage and anaphylactic shock, pinpointing this pathway as a target for barrier-protective therapies.

During sprouting angiogenesis, VEGF-driven cell elongation triggers polarised actin lamellipodia that remodel VE-cadherin distribution at junctions, balancing cell migration with monolayer integrity. These intermittent protrusions, controlled by actin-nucleating complexes, form new adhesion sites and reconcile vessel growth with barrier maintenance.

Endothelial Junction Regulation and Vascular Integrity publication trend

The graph below shows the total number of articles in endothelial junction regulation and vascular integrity across all publications each year (not limited to Nature Index journals).

Technical terms

Adherens junction: A cell–cell adhesion complex in endothelium, centred on VE-cadherin and catenins, that links neighbouring cells to the actin cytoskeleton and governs paracellular integrity.

Tight junction: A seal of claudins, occludin and junctional adhesion molecules that controls selective permeability across the endothelium.

VE-cadherin: Vascular endothelial cadherin, a transmembrane adhesion protein essential for adherens junction formation and vascular barrier stability.

Ubiquitin E3 ligase: An enzyme that tags target proteins with ubiquitin, marking them for proteasomal degradation and regulating protein turnover at cell junctions.

RhoA GTPase: A small GTP-binding protein that orchestrates actomyosin contractility and cytoskeletal tension, critical for junctional remodelling.

References

1. Ubiquitin ligase CHFR mediated degradation of VE-cadherin through ubiquitylation disrupts endothelial adherens junctions. Nature Communications (2023).
2. RhoA and ROCK mediate histamine-induced vascular leakage and anaphylactic shock. Nature Communications (2015).
3. Polarized actin and VE-cadherin dynamics regulate junctional remodelling and cell migration during sprouting angiogenesis. Nature Communications (2017).
4. Integrin-Dependent Cell–Matrix Adhesion in Endothelial Health and Disease. Circulation Research (2023).
5. IL-33 via PKCμ/PRKD1 Mediated α-Catenin Phosphorylation Regulates Endothelial Cell-Barrier Integrity and Ischemia-Induced Vascular Leakage. Cells (2023).
6. Alveolar-capillary endocytosis and trafficking in acute lung injury and acute respiratory distress syndrome. Frontiers in Immunology (2024).