Abstract
We investigated the effects of NO on angiogenesis and the synthesis of vascular endothelial growth factor (VEGF) in a model of focal embolic cerebral ischemia in the rat. Compared with control rats, systemic administration of an NO donor, DETANONOate, to rats 24 hours after stroke significantly enlarged vascular perimeters and increased the number of proliferated cerebral endothelial cells and the numbers of newly generated vessels in the ischemic boundary regions, as evaluated by 3-dimensional laser scanning confocal microscopy. Treatment with DETANONOate significantly increased VEGF levels in the ischemic boundary regions as measured by ELISA. A capillary-like tube formation assay was used to investigate whether DETANONOate increases angiogenesis in ischemic brain via activation of soluble guanylate cyclase. DETANONOate-induced capillary-like tube formation was completely inhibited by a soluble guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ). Blocking VEGF activity by a neutralized antibody against VEGF receptor 2 significantly attenuated DETANONOate-induced capillary-like tube formation. Moreover, systemic administration of a phosphodiesterase type 5 inhibitor (Sildenafil) to rats 24 hours after stroke significantly increased angiogenesis in the ischemic boundary regions. Sildenafil and an analog of cyclic guanosine monophosphate (cGMP) also induced capillary-like tube formation. These findings suggest that exogenous NO enhances angiogenesis in ischemic brain, which is mediated by the NO/cGMP pathway. Furthermore, our data suggest that NO, in part via VEGF, may enhance angiogenesis in ischemic brain.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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3',5'-Cyclic-GMP Phosphodiesterases / antagonists & inhibitors
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Animals
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Brain / blood supply
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Brain / drug effects
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Brain / pathology
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Bromodeoxyuridine
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Cell Division / drug effects
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Cyclic GMP / biosynthesis*
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Cyclic Nucleotide Phosphodiesterases, Type 5
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Disease Models, Animal
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Endothelial Growth Factors / biosynthesis*
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / pathology
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Enzyme Inhibitors / pharmacology
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Guanylate Cyclase
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Intercellular Signaling Peptides and Proteins / biosynthesis*
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Lymphokines / biosynthesis*
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Male
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Neovascularization, Physiologic / drug effects
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Neovascularization, Physiologic / physiology*
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Nitric Oxide / metabolism
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Nitric Oxide / pharmacology*
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Nitric Oxide Donors / pharmacology
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Nitroso Compounds / pharmacology
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Piperazines / pharmacology
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Purines
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Rats
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Rats, Wistar
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Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors
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Sildenafil Citrate
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Soluble Guanylyl Cyclase
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Stroke / drug therapy
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Stroke / metabolism*
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Stroke / pathology
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Sulfones
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
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Vascular Endothelial Growth Factors
Substances
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Endothelial Growth Factors
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Enzyme Inhibitors
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Intercellular Signaling Peptides and Proteins
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Lymphokines
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Nitric Oxide Donors
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Nitroso Compounds
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Piperazines
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Purines
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Receptors, Cytoplasmic and Nuclear
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Sulfones
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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2,2'-(hydroxynitrosohydrazono)bis-ethanamine
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Nitric Oxide
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Sildenafil Citrate
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Vascular Endothelial Growth Factor Receptor-2
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3',5'-Cyclic-GMP Phosphodiesterases
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Cyclic Nucleotide Phosphodiesterases, Type 5
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Pde5a protein, rat
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Guanylate Cyclase
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Soluble Guanylyl Cyclase
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Bromodeoxyuridine
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Cyclic GMP