Abstract: Objective To determine the effect of sphingosine-1-phosphate receptor 2 (S1PR2) on vascular permeability in mice. Methods Acute lung injury models of mice were constructed with intra-tracheal administration of lipopolysaccharide (LPS) and compared with the controls with intra-tracheal administration of saline. The effect of S1PR2 on vascular permeability was observed by detecting leakage of Evans blue into lung tissues, pulmonary vascular leakage of fluorescein isothiocyanate （FITC）-dextran, and the wet/dry mass ratio of lungs. The effect of vascular endothelial growth factor （VEGF） on vascular endothelial permeability was detected by Miles analysis. Results LPS injections induced significant Evans blue leakage, FITC-dextran pulmonary vascular leakage and pulmonary edema, which appeared to be more serious in S1PR2-deleted mice compared with those in wild-type mice. LPS enhanced Evans blue leakage associated with VEGF in a dose-dependent way in both S1PR2-deleted mice and wild type mice. But the vascular permeability response in subcutaneous tissues induced by VEGF was higher in S1PR2-deleted mice than that in wild-type mice. Conclusion S1PR2 is involved in endothelial cell barrier protections, which inhibits vascular permeability.