Soluble Flt-1 gene transfer ameliorates neointima formation after wire injury in flt-1 tyrosine kinase-deficient mice.
OBJECTIVE
We have demonstrated that vascular endothelial growth factor (VEGF) expression is upregulated in injured vascular wall, and blockade of VEGF inhibited monocyte infiltration and neointima formation in several animal models. In the present study, we aimed to clarify relative role of two VEGF receptors, flt-1 versus flk-1/KDR, in neointima formation after injury using flt-1 tyrosine kinase-deficient (Flt-1 TK(-/-)) mice and soluble Flt-1(sFlt-1) gene transfer.


RESULTS
Neointima formation was comparable between wild-type and Flt-1 TK(-/-) mice 28 days after intraluminal wire injury in femoral arteries. By contrast, neointima formation was significantly suppressed by sFlt-1 gene transfer into Flt-1 TK(-/-) mice that blocks VEGF action on flk-1 (intima/media ratio: 2.8+/-0.4 versus 1.4+/-0.4, P<0.05). The inhibition of neointima formation was preceded by significant reduction of monocyte chemoattractant protein (MCP-1) expression in vascular smooth muscle cells (VSMCs) and monocyte infiltration 7 days after injury. Gene transfer of sFlt-1 or treatment of flk-1-specific antibody significantly inhibited VEGF-induced MCP-1 expression determined by RT-PCR in cultured aortic tissue and VSMCs. MCP-1-induced chemotaxis was equivalent between wild-type and Flt-1 TK(-/-) mice.


CONCLUSIONS
These results suggest that endogenous VEGF accelerates neointima formation through flk-1 by regulating MCP-1 expression in VSMCs and macrophage-mediated inflammation in injured vascular wall in murine model of wire injury.
Koga
Jun-ichiro
J
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
Matoba
Tetsuya
T
Egashira
Kensuke
K
Kubo
Mitsuki
M
Miyagawa
Miho
M
Iwata
Eiko
E
Sueishi
Katsuo
K
Shibuya
Masabumi
M
Sunagawa
Kenji
K
D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D003251:Constriction, Pathologic; D004195:Disease Models, Animal; D018274:Electroporation; D005263:Femoral Artery / Q000201:enzymology* / Q000293:injuries / Q000473:pathology; D018014:Gene Transfer Techniques; D006965:Hyperplasia; D017737:Macrophages, Peritoneal / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000293:injuries / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology; D018919:Neovascularization, Physiologic; D046509:Tissue Culture Techniques; D017539:Tunica Intima / Q000201:enzymology* / Q000293:injuries / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2