VEGF increases permeability of the blood-brain barrier via a nitric oxide synthase/cGMP-dependent pathway.
It appears that the expression of vascular endothelial growth factor (VEGF) is increased during brain injury and thus may contribute to disruption of the blood-brain barrier (BBB) during cerebrovascular trauma. The first goal of this study was to determine the effect of VEGF on permeability of the BBB in vivo. The second goal was to determine possible cellular mechanisms by which VEGF increases permeability of the BBB. We examined the pial microcirculation in rats using intravital fluorescence microscopy. Permeability of the BBB [clearance of FITC-labeled dextran of molecular mass 10,000 Da (FITC-dextran-10K)] and diameter of pial arterioles were measured in absence and presence of VEGF (0.01 and 0.1 nM). During superfusion with vehicle (saline), clearance of FITC-dextran-10K from pial vessels was minimal and diameter of pial arterioles remained constant. Topical application of VEGF (0.01 nM) did not alter permeability of the BBB to FITC-dextran-10K or arteriolar diameter. However, superfusion with VEGF (0.1 nM) produced a marked increase in clearance of FITC-dextran-10K and a modest dilatation of pial arterioles. To determine a potential role for nitric oxide and stimulation of soluble guanylate cyclase in VEGF-induced increases in permeability of the BBB and arteriolar dilatation, we examined the effects of NG-monomethyl-L-arginine (L-NMMA; 10 microM) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 1.0 microM), respectively. L-NMMA and ODQ inhibited VEGF-induced increases in permeability of the BBB and arteriolar dilatation. The findings of the present study suggest that VEGF, which appears to be increased in brain tissue during cerebrovascular trauma, increases the permeability of the BBB via the synthesis/release of nitric oxide and subsequent activation of soluble guanylate cyclase.
D000818:Animals; D001160:Arterioles / Q000033:anatomy & histology; D001812:Blood-Brain Barrier; D002199:Capillary Permeability; D006152:Cyclic GMP / Q000494:pharmacology*; D003911:Dextrans / Q000378:metabolism; D016228:Endothelial Growth Factors / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000378:metabolism; D007700:Kinetics; D008222:Lymphokines / Q000494:pharmacology*; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010841:Pia Mater / Q000098:blood supply; D051381:Rats; D011920:Rats, Inbred WF; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019323:omega-N-Methylarginine / Q000494:pharmacology