Ninjurin2 Promotes Pulmonary Endothelial Barrier Dysfunction Through VEGF/VEGFR2 Signaling Pathway

Area of Science:

• Vascular Biology
• Cellular Biology
• Pathophysiology

Background:

• Ninjurin2 is linked to vascular endothelial dysfunction in diseases like stroke and heart disease.
• Impaired pulmonary endothelial barrier function is a hallmark of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS).

Purpose of the Study:

• To investigate the role of Ninjurin2 in regulating lung vascular permeability and endothelial cell function in ALI and ARDS.
• To elucidate the underlying molecular mechanisms by which Ninjurin2 influences endothelial barrier integrity.

Main Methods:

• Utilized endothelial-specific Ninjurin2 overexpressing mice (NINJ2-TG^EC) and control littermates.
• Assessed vascular permeability using Evans Blue dye extravasation and FITC-dextran flux assays.
• Investigated protein interactions and signaling pathways via co-immunoprecipitation (Co-IP) and Western blotting, focusing on Ninjurin2 and VEGFR2.

Main Results:

• NINJ2-TG^EC mice exhibited severe lung injury and increased vascular permeability.
• Ninjurin2 overexpression disrupted endothelial adherens and tight junctions (VE-cadherin, ZO-1) and increased permeability.
• Ninjurin2 directly bound to VEGFR2, activating VEGFR2/AKT signaling and enhancing VEGF165-induced barrier dysfunction.
• Inhibition of VEGFR2 reversed Ninjurin2-mediated vascular leakage and lung pathology.
• Ninjurin2 overexpression promoted ROS accumulation, AKT/NF-κB/ICAM-1 activation, and monocyte-endothelial adhesion.

Conclusions:

• Ninjurin2 compromises endothelial barrier integrity and promotes vascular inflammation via a VEGFR2-dependent mechanism.
• Ninjurin2 exacerbates vascular hyperpermeability, particularly in the lungs, by interacting with VEGFR2 and activating VEGF/VEGFR2 signaling.
• Ninjurin2 represents a potential therapeutic target for ALI and ARDS.