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 B BB in vivo. The second goal was to determine possible cellular mechanisms b y which VEGF increases permeability of the BBB. We examined the pial microc irculation in rats using intravital fluorescence microscopy. Permeability o f the BBB [clearance of FITC-labeled dextran of molecular mass 10,000 Da (F ITC-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 (sa line), clearance of FITC-dextran-10K from pial vessels was minimal and diam eter of pial arterioles remained constant. Topical application of VEGF (0.0 1 nM) did not alter permeability of the BBB to FITC-dextran-10K or arteriol ar diameter. However, superfusion with VEGF (0.1 nM) produced a marked incr ease in clearance of FITC-dextran-10K and a modest dilatation of pial arter ioles. To determine a potential role for nitric oxide and stimulation of so luble guanylate cyclase in VEGF-induced increases in permeability of the BB B and arteriolar dilatation, we examined the effects of N-G-monomethyl-L-ar ginine (L-NMMA; 10 mu M) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (O DQ; 1.0 mu M), respectively. L-NMMA and ODQ inhibited VEGF-induced increase s in permeability of the BBB and arteriolar dilatation. The findings of the present study suggest that VEGF, which appears to be increased in brain ti ssue during cerebrovascular trauma, increases the permeability of the BBB v ia the synthesis/release of nitric oxide and subsequent activation of solub le guanylate cyclase.