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VEGF is a key regulator of vascular permeability. However, its signaling pathways are incompletely understood. We tested the hypothesis that VEGF regulates endothelial cell (EC) permeability by activating PKB/akt, NOS, and MAP kinase dependent pathways using human umbilical vein EC (HUVEC). Permeability was measured from FITC–dextran 70-kDa flux across the EC monolayer at baseline and after VEGF at 0.034, 0.068, 1, 10, and 100 nM. VEGF increased HUVEC permeability to FITC–dextran in a dose-dependent manner. VEGF (1 nM) increased permeability from 3.9 × 10⁻⁶ ± 0.7 × 10⁻⁶ to 14.0 × 10⁻⁶ ± 1.7 × 10⁻⁶ cm/s (mean ± SEM; P < 0.001). Permeability changes were also assessed after treatment with 1, 10, and 100 nM wortmannin (PI 3-kinase inhibitor); 0.01, 0.1, and 1.0 nM LY294002 (PI 3-kinase inhibitor); 200 μM l -NMMA (NOS inhibitor); 2.7 μM AG126 (p42/44^MAPK inhibitor); and 0.006, 0.06 …