The Robo4-TRAF7 complex suppresses endothelial hyperpermeability in inflammation.

Area of Science:

• Endothelial cell biology
• Vascular biology
• Inflammation research

Background:

• Roundabout guidance receptor 4 (Robo4) is an endothelial cell-specific receptor known to stabilize vasculature during pathological angiogenesis.
• While Robo4's role in suppressing vascular endothelial growth factor (VEGF)-induced hyperpermeability is established, its function in inflammation remains unclear.

Purpose of the Study:

• To investigate the role of Robo4 in regulating vascular hyperpermeability during inflammatory conditions.
• To elucidate the molecular mechanisms underlying Robo4's function in inflammation.

Main Methods:

• Utilized endotoxemia models in Robo4-deficient (Robo4-/-) mice.
• Performed experiments on endothelial cells, including studies on tumor necrosis factor α (TNFα)-induced hyperpermeability, VE-cadherin localization, and binding assays.
• Conducted gain- and loss-of-function studies for TNF receptor-associated factor 7 (TRAF7).

Main Results:

• Robo4-deficient mice exhibited increased mortality and vascular leakage in endotoxemia models.
• Robo4 suppressed TNFα-induced hyperpermeability in endothelial cells by stabilizing VE-cadherin at cell junctions, with the C-terminus of Robo4 being crucial for this effect.
• Robo4 directly binds to TRAF7 via its C-terminus in endothelial cells.
• TRAF7 is essential for Robo4-mediated suppression of inflammatory hyperpermeability.

Conclusions:

• The Robo4-TRAF7 complex acts as a novel negative regulator of inflammatory vascular hyperpermeability.
• This complex represents a potential therapeutic target for mitigating damage in inflammatory diseases.