Abstract
Background:
It remains unclear whether vascular endothelial growth factor (VEGF) is a proarteriosclerotic or an antiarteriosclerotic factor. We recently reported that long-term inhibition of nitric oxide by administering Nomega-nitro-L-arginine methyl ester (L-NAME) induces coronary vascular inflammation and arteriosclerosis.
Methods and results:
We used this animal model to investigate the role of VEGF in arteriosclerosis. We blocked VEGF activity in vivo by transfecting with plasmid DNA encoding the murine soluble FLT-1 (sFLT-1) gene into thigh muscle. Soluble FLT-1 can suppress VEGF activity both by sequestering VEGF and by functioning as a dominant-negative inhibitor of VEGF receptors. We observed vascular inflammation associated with increased VEGF expression within 3 days of L-NAME administration, which was prevented by pretreatment with ACE inhibitor, angiotensin II receptor antagonist, or neutralizing monocyte chemoattractant protein-1 antibody. The sFLT-1 gene transfer attenuated the early vascular inflammation and prevented late arteriosclerosis. The sFLT-1 gene transfer also inhibited increased expression of monocyte chemoattractant protein-1 and transforming growth factor-beta, indicating creation of a positive feedback loop to cause arteriosclerosis.
Conclusions:
VEGF is necessary in the development of arteriosclerosis by mediating monocyte recruitment and activation in this model.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Arteriosclerosis / etiology
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Arteriosclerosis / immunology
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Arteriosclerosis / metabolism*
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Arteriosclerosis / pathology
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Biological Assay
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Blood Pressure / drug effects
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Cell Division / drug effects
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Chemokine CCL2 / genetics
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Chemokine CCL2 / metabolism
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Chemotaxis, Leukocyte / drug effects
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Coronary Vessels / drug effects
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Coronary Vessels / immunology
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Coronary Vessels / pathology
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Disease Models, Animal
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Endothelial Growth Factors / antagonists & inhibitors
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Endothelial Growth Factors / metabolism*
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Enzyme Inhibitors / administration & dosage
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Gene Expression / drug effects
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Gene Transfer, Horizontal
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Genetic Vectors / administration & dosage
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Genetic Vectors / biosynthesis
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Genetic Vectors / genetics
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Inflammation / immunology
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Inflammation / pathology
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Injections, Intramuscular
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Lymphokines / antagonists & inhibitors
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Lymphokines / metabolism*
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Male
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Mice
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Monocytes / immunology
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Monocytes / metabolism*
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Monocytes / pathology
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NG-Nitroarginine Methyl Ester / administration & dosage
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Neovascularization, Physiologic / drug effects
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Nitric Oxide / antagonists & inhibitors*
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Nitric Oxide / blood
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Peptidyl-Dipeptidase A / metabolism
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Proto-Oncogene Proteins / administration & dosage*
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Proto-Oncogene Proteins / biosynthesis
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Proto-Oncogene Proteins / genetics
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RNA, Messenger / biosynthesis
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Rats
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Rats, Inbred WKY
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Receptor Protein-Tyrosine Kinases / administration & dosage*
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Receptor Protein-Tyrosine Kinases / biosynthesis
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Receptor Protein-Tyrosine Kinases / genetics
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Time
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / metabolism
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factor Receptor-1
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Vascular Endothelial Growth Factors
Substances
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Chemokine CCL2
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Endothelial Growth Factors
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Enzyme Inhibitors
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Lymphokines
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Proto-Oncogene Proteins
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RNA, Messenger
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Transforming Growth Factor beta
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Nitric Oxide
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Receptor Protein-Tyrosine Kinases
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Vascular Endothelial Growth Factor Receptor-1
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Peptidyl-Dipeptidase A
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NG-Nitroarginine Methyl Ester