VEGF165b attenuates LPS-induced acute lung injury via antagonizing the VEGF165a/VEGFR2 signaling pathway.

Vascular endothelial growth factor (VEGF) plays a central role in the pathogenesis of acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), yet targeted therapies for these conditions remain elusive. This study identified the VEGF-A splice variant VEGF165b as a crucial endogenous protector against ALI/ARDS. In patients, the circulating ratio of VEGF165b to total VEGF-A was significantly reduced and correlated inversely with disease severity. In murine models of LPS-induced ALI, administration of exogenous VEGF165b alleviated pulmonary edema, inflammation, and injury, whereas its neutralization exacerbated damage. Mechanistically, VEGF165b functioned as a competitive antagonist, selectively inhibiting VEGF165a-induced phosphorylation of VEGFR2 at tyrosine 1175. This blockade suppressed the downstream PI3K/AKT/eNOS permeability pathway, reducing SRC-mediated VE-cadherin phosphorylation and thereby enhancing endothelial barrier integrity. Additionally, VEGF165b downregulated the chemokine CCL2, limiting monocyte-endothelial adhesion through a distinct anti-inflammatory mechanism. Our findings established VEGF165b as a key endogenous stabilizer of the vascular barrier, acting via dual pathways-direct junctional reinforcement and anti-inflammatory activity-and highlighted its potential as both a biomarker and a therapeutic agent for ALI/ARDS. This work revealed the critical balance of VEGF splicing variants in vascular homeostasis and offers a novel strategy for treating vascular barrier dysfunction in critical lung diseases.