SCUBE2 regulates adherens junction dynamics and vascular barrier function during inflammation

Area of Science:

• Endothelial cell biology
• Vascular biology
• Molecular mechanisms of cell adhesion

Background:

• SCUBE2 (signal peptide-CUB-epidermal growth factor-like domain-containing protein 2) is known to stabilize epithelial adherens junctions.
• Its role in endothelial cells and vascular barrier function is not well understood.

Purpose of the Study:

• To investigate the role of SCUBE2 in endothelial cells (ECs) in maintaining vascular barrier function.
• To determine the molecular mechanisms by which SCUBE2 regulates EC adherens junctions (AJs).

Main Methods:

• Investigated SCUBE2 interaction with VE-cadherin and VE-PTP in ECs.
• Utilized SCUBE2 knockdown and EC-specific knockout (EC-KO) and overexpression mouse models.
• Analyzed effects of SCUBE2 modulation on EC permeability, VE-cadherin phosphorylation, and endocytosis.
• Examined SCUBE2 expression regulation by the nuclear factor-κB pathway.

Main Results:

• SCUBE2 interacts with VE-cadherin and VE-PTP at EC AJs, stabilizing them.
• SCUBE2 knockdown or EC-KO increased EC permeability and vascular leakiness.
• SCUBE2 deficiency led to VE-cadherin hyperphosphorylation and endocytosis.
• SCUBE2 expression is downregulated by inflammatory signaling via NF-κB.
• SCUBE2 overexpression protected against vascular leakage in inflammatory conditions.

Conclusions:

• SCUBE2 is crucial for vascular integrity by stabilizing EC AJs through VE-PTP recruitment and VE-cadherin dephosphorylation.
• SCUBE2 modulation offers a potential therapeutic strategy for preventing vascular leakage in inflammatory diseases.