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

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Abstract

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 N(G)-monomethyl-L-arginine (L-NMMA; 10 μM) and 1H-[1,2,4]oxadiazolo[4,3- a]quinoxalin-1-one (ODQ; 1.0 μM), 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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Cell Physiology
Volume276
Issue number5 45-5
StatePublished - Jun 5 1999

Fingerprint

Blood-Brain Barrier
Nitric Oxide Synthase
Vascular Endothelial Growth Factor A
Permeability
Cerebrovascular Trauma
Arterioles
omega-N-Methylarginine
Dilatation
Nitric Oxide
Microcirculation
Fluorescence Microscopy
Brain Injuries
Arginine
fluorescein isothiocyanate dextran
Brain

Keywords

  • Cerebral venules
  • Fluorescein isothiocyanate-dextran
  • N(G)-monomethyl-L-arginine
  • Pial arterioles
  • Soluble guanylate cyclase
  • Vascular endothelial cell growth factor

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

Cite this

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title = "VEGF increases permeability of the blood-brain barrier via a nitric oxide synthase/cGMP-dependent pathway",
abstract = "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 N(G)-monomethyl-L-arginine (L-NMMA; 10 μM) and 1H-[1,2,4]oxadiazolo[4,3- a]quinoxalin-1-one (ODQ; 1.0 μM), 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.",
keywords = "Cerebral venules, Fluorescein isothiocyanate-dextran, N(G)-monomethyl-L-arginine, Pial arterioles, Soluble guanylate cyclase, Vascular endothelial cell growth factor",
author = "William Mayhan",
year = "1999",
month = "6",
day = "5",
language = "English (US)",
volume = "276",
journal = "American Journal of Physiology - Renal Physiology",
issn = "0363-6127",
publisher = "American Physiological Society",
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TY - JOUR

T1 - VEGF increases permeability of the blood-brain barrier via a nitric oxide synthase/cGMP-dependent pathway

AU - Mayhan, William

PY - 1999/6/5

Y1 - 1999/6/5

N2 - 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 N(G)-monomethyl-L-arginine (L-NMMA; 10 μM) and 1H-[1,2,4]oxadiazolo[4,3- a]quinoxalin-1-one (ODQ; 1.0 μM), 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.

AB - 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 N(G)-monomethyl-L-arginine (L-NMMA; 10 μM) and 1H-[1,2,4]oxadiazolo[4,3- a]quinoxalin-1-one (ODQ; 1.0 μM), 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.

KW - Cerebral venules

KW - Fluorescein isothiocyanate-dextran

KW - N(G)-monomethyl-L-arginine

KW - Pial arterioles

KW - Soluble guanylate cyclase

KW - Vascular endothelial cell growth factor

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M3 - Article

VL - 276

JO - American Journal of Physiology - Renal Physiology

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