Vascular endothelial growth factor is necessary in the development of arteriosclerosis by recruiting/activating monocytes in a rat model of long-term inhibition of nitric oxide synthesis.
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.


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.
Zhao
Qingwei
Q
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Egashira
Kensuke
K
Inoue
Shujiro
S
Usui
Makoto
M
Kitamoto
Shiro
S
Ni
Weihua
W
Ishibashi
Minako
M
Hiasa Ki
Ken-ichi
K
Ichiki
Toshihiro
T
Shibuya
Masabumi
M
Takeshita
Akira
A
D000818:Animals; D001161:Arteriosclerosis / Q000209:etiology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D001681:Biological Assay; D001794:Blood Pressure / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D015870:Gene Expression / Q000187:drug effects; D022761:Gene Transfer, Horizontal; D005822:Genetic Vectors / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D007273:Injections, Intramuscular; D008222:Lymphokines / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D051379:Mice; D009000:Monocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000097:blood; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011921:Rats, Inbred WKY; D020794:Receptor Protein-Tyrosine Kinases / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics; D013995:Time; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D042442:Vascular Endothelial Growth Factors
D018932:Chemokine CCL2; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D008222:Lymphokines; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D009569:Nitric Oxide; D020794:Receptor Protein-Tyrosine Kinases; D040281:Vascular Endothelial Growth Factor Receptor-1; D007703:Peptidyl-Dipeptidase A; D019331:NG-Nitroarginine Methyl Ester