The adaptation of the blood-brain barrier to vascular endothelial growth factor and placental growth factor during pregnancy.

Vascular endothelial growth factor (VEGF) and placental growth factor (PLGF) are increased in the maternal circulation during pregnancy. These factors may increase blood-brain barrier (BBB) permeability, yet brain edema does not normally occur during pregnancy. We therefore hypothesized that in pregnancy, the BBB adapts to high levels of these permeability factors. We investigated the influence of pregnancy-related circulating factors on VEGF-induced BBB permeability by perfusing cerebral veins with plasma from nonpregnant (NP) or late-pregnant (LP) rats (n=6/group) and measuring permeability in response to VEGF. The effect of VEGF, PLGF, and VEGF-receptor (VEGFR) activation on BBB permeability was also determined. Results showed that VEGF significantly increased permeability (×10(7) μm(3)/min) from 9.7 ± 3.5 to 21.0 ± 1.5 (P<0.05) in NP veins exposed to NP plasma, that was prevented when LP veins were exposed to LP plasma; (9.7±3.8; P>0.05). Both LP plasma and soluble FMS-like tyrosine-kinase 1 (sFlt1) in NP plasma abolished VEGF-induced BBB permeability in NP veins (9.5±2.9 and 12±2.6; P>0.05). PLGF significantly increased BBB permeability in NP plasma (18±1.4; P<0.05), and required only VEGFR1 activation, whereas VEGF-induced BBB permeability required both VEGFR1 and VEGFR2. Our findings suggest that VEGF and PLGF enhance BBB permeability through different VEGFR pathways and that circulating sFlt1 prevents VEGF- and PLGF-induced BBB permeability during pregnancy.