Endothelial Cell Junction Dynamics in Vascular Integrity

Endothelial cell junctions form a dynamic interface that governs vascular permeability, tissue perfusion and homeostasis. The principal adhesive structures—adherens junctions and tight junctions—are linked to the actin cytoskeleton and respond to mechanical and chemical stimuli by remodelling their protein composition and organisation. Actomyosin contractility, regulated by small GTPases and kinase pathways, tunes junctional tension to permit controlled opening or stabilisation of the vascular barrier. Coordination between junctional adhesion molecules, such as VE-cadherin, and cortical actin polymerisation underpins processes as diverse as lumen formation, barrier restoration after inflammation and cell rearrangement during angiogenesis. Disruption of these mechanisms contributes to pathological leakage, oedema and aberrant vascular growth, whereas their modulation offers routes to therapeutic control of vascular integrity in disease settings.

Research from Nature Portfolio

Recent studies have elucidated how junctional contractility is locally regulated to initiate and sustain lumen formation. In a vertebrate model, the endothelial-specific protein Rasip1 was shown to be recruited to nascent junctional patches where it inhibits non-muscle myosin II, suppressing local contractility and allowing apical domain expansion. Rasip1 dynamically shuttles between junctions and apical compartments in response to mechanical tension, stabilising VE-cadherin clusters and ensuring lumen continuity. Complementary work has revealed a cAMP-dependent stabilisation of cortical actin via the PKA substrate ZNF185. Upon PKA activation, ZNF185 associates with membrane-proximal F-actin, reinforcing junctional architecture and counteracting RhoA-driven stress fibre formation. Loss of ZNF185 leads to constitutive RhoA activity, junctional disassembly and increased vascular leakage in inflammatory models, emphasising its essential role in barrier maintenance. Further insights into junctional motility have come from high-resolution imaging of junction-based lamellipodia. Oscillatory protrusions enriched in VE-cadherin and F-actin drive endothelial cell rearrangements, with Rac1-dependent cycles of protrusion and adhesion facilitating collective cell movement during vessel remodelling.

Endothelial Cell Junction Dynamics in Vascular Integrity publication trend

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

Technical terms

Adherens junction: A cell–cell adhesion complex anchored to actin filaments via cadherins, crucial for mechanical stability of the endothelium.

VE-cadherin: A transmembrane cadherin family protein specific to endothelial cells, central to adherens junction formation and barrier function.

Tight junction: A specialised membrane contact between endothelial cells that limits paracellular permeability through claudins and occludins.

Actomyosin contractility: Force generation by actin and myosin interactions, modulating tension at cell junctions.

Rasip1: An endothelial-specific Rap1 effector that regulates junctional contractility and lumenogenesis by inhibiting non-muscle myosin II.

RhoA: A small GTPase that promotes stress fibre formation and junctional tension via ROCK activation.

Cortical actin: A network of actin filaments beneath the plasma membrane that supports cell shape and junctional stability.

References

1. Initiation of lumen formation from junctions via differential actomyosin contractility regulated by dynamic recruitment of Rasip1. Nature Communications (2024).
2. ZNF185 prevents stress fiber formation through the inhibition of RhoA in endothelial cells. Communications Biology (2023).
3. Junction-based lamellipodia drive endothelial cell rearrangements in vivo via a VE-cadherin-F-actin based oscillatory cell-cell interaction. Nature Communications (2018).
4. Activation of Vascular Endothelial Growth Factor (VEGF) Receptor 2 Mediates Endothelial Permeability Caused by Cyclic Stretch*. Journal of Biological Chemistry (2016).
5. Heart of glass anchors Rasip1 at endothelial cell-cell junctions to support vascular integrity. eLife (2016).