VEGF increases permeability of the blood-brain barrier via a nitric oxide synthase/cGMP-dependent pathway

It appears thatthe expression of vascular endothelial growth factor (VEGF) isincreased during brain injury and thus may contribute to disruption ofthe blood-brain barrier (BBB) during cerebrovascular trauma. The firstgoal of this study was to determine the effect of VEGF on permeabilityof the BBB in vivo. The second goal was to determine possible cellularmechanisms by which VEGF increases permeability of the BBB. We examinedthe pial microcirculation in rats using intravital fluorescencemicroscopy. Permeability of the BBB [clearance of FITC-labeleddextran of molecular mass 10,000 Da (FITC-dextran-10K)] anddiameter of pial arterioles were measured in absence and presence ofVEGF (0.01 and 0.1 nM). During superfusion with vehicle (saline),clearance of FITC-dextran-10K from pial vessels was minimal anddiameter of pial arterioles remained constant. Topical application ofVEGF (0.01 nM) did not alter permeability of the BBB toFITC-dextran-10K or arteriolar diameter. However, superfusion with VEGF(0.1 nM) produced a marked increase in clearance of FITC-dextran-10Kand a modest dilatation of pial arterioles. To determine a potentialrole for nitric oxide and stimulation of soluble guanylate cyclase inVEGF-induced increases in permeability of the BBB and arteriolardilatation, we examined the effects ofN^G-monomethyl-L-arginine(L-NMMA; 10 µM) and1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 1.0 µM), respectively.L-NMMA and ODQ inhibitedVEGF-induced increases in permeability of the BBB and arteriolardilatation. The findings of the present study suggest that VEGF, whichappears to be increased in brain tissue during cerebrovascular trauma, increases the permeability of the BBB via the synthesis/release ofnitric oxide and subsequent activation of soluble guanylate cyclase.