Essential role of vascular endothelial growth factor and Flt-1 signals in neointimal formation after periadventitial injury.
OBJECTIVE
Vascular endothelial growth factor (VEGF) is upregulated after arterial injury. Its role in the pathogenesis of neointimal formation after periadventitial injury, however, has not been addressed.


RESULTS
Expression of VEGF and its receptors but not that of placental growth factor markedly increased with the development of neointimal formation in hypercholesterolemic mice after cuff-induced periarterial injury. Transfection with the murine soluble Flt-1 (sFlt-1) gene to block VEGF in vivo in mice inhibited early inflammation and later neointimal formation. The sFlt-1 gene transfer did not affect plasma lipid levels but attenuated increased expression of VEGF, Flt-1, Flk-1, monocyte chemoattractant protein-1, and other inflammation-promoting factors. Mice with Flt-1 kinase deficiency also displayed reduced neointimal formation.


CONCLUSIONS
Inflammatory changes mediated by VEGF and Flt-1 signals play an important role in the pathogenesis of neointimal formation after cuff-induced periadventitial injury. VEGF might promote neointimal formation by acting as a proinflammatory cytokine.
Zhao
Qingwei
Q
Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan.
Egashira
Kensuke
K
Hiasa
Ken-ichi
K
Ishibashi
Minako
M
Inoue
Shujiro
S
Ohtani
Kisho
K
Tan
Chunyan
C
Shibuya
Masabumi
M
Takeshita
Akira
A
Sunagawa
Kenji
K
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000502:physiology; D005263:Femoral Artery / Q000737:chemistry / Q000293:injuries / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D018014:Gene Transfer Techniques; D006965:Hyperplasia / Q000097:blood / Q000201:enzymology; D007150:Immunohistochemistry / Q000379:methods; D008055:Lipids / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000502:physiology*; D020033:Protein Isoforms / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D012995:Solubility; D013997:Time Factors; D017539:Tunica Intima / Q000473:pathology / Q000502:physiology*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis / Q000276:immunology; D042442:Vascular Endothelial Growth Factors / Q000235:genetics
D001057:Apolipoproteins E; D008055:Lipids; D020033:Protein Isoforms; D042442:Vascular Endothelial Growth Factors; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2