title: Involvement of Flt-1 tyrosine kinase (vascular endothelial growth factor receptor-1) in pathological angiogenesis.
abstract: Vascular endothelial growth factor (VEGF) and its two receptors, Fms-like tyrosine kinase 1 (Flt-1) (VEGFR-1) and KDR/Flk-1 (VEGFR-2), have been demonstrated to be an essential regulatory system for blood vessel formation in mammals. KDR is a major positive signal transducer for angiogenesis through its strong tyrosine kinase activity. Flt-1 has a unique biochemical activity, 10-fold higher affinity to VEGF, whereas much weaker tyrosine kinase activity compared with KDR. Recently, we and others have shown that Flt-1 has a negative regulatory function for physiological angiogenesis in the embryo, possibly with its strong VEGF-trapping activity. However, it is still open to question whether the tyrosine kinase of Flt-1 has any positive role in angiogenesis at adult stages. In this study, we examined whether Flt-1+ could be a positive signal transducer under certain pathological conditions, such as angiogenesis with tumors overexpressing a Flt-1-specific, VEGF-related ligand. Our results show clearly that murine Lewis lung carcinoma cells overexpressing placenta growth factor-2, an Flt-1-specific ligand, grew in wild-type mice much faster than in Flt-1 tyrosine kinase domain-deficient mice. Blood vessel formation in tumor tissue was higher in wild-type mice than in Flt-1 tyrosine kinase-deficient mice. On the other hand, the same carcinoma cells overexpressing VEGF showed no clear difference in the tumor growth rate between these two genotypes of mice. These results indicate that Flt-1 is a positive regulator using its tyrosine kinase under pathological conditions when the Flt-1-specific ligand is abnormally highly expressed. Thus, Flt-1 has a dual function in angiogenesis, acting in a positive or negative manner in different biological conditions.
authors.affiliation: Department of Genetics, Institute of Medical Science, University of Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Hiratsuka
authors.forename: Y
authors.initials: Y
authors.lastname: Maru
authors.forename: A
authors.initials: A
authors.lastname: Okada
authors.forename: M
authors.initials: M
authors.lastname: Seiki
authors.forename: T
authors.initials: T
authors.lastname: Noda
authors.forename: M
authors.initials: M
authors.lastname: Shibuya
mesh_terms: D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000473:pathology; D002455:Cell Division / Q000502:physiology; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006801:Humans; D008024:Ligands; D008222:Lymphokines / Q000096:biosynthesis / Q000235:genetics; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018995:Myosin Heavy Chains; D009389:Neovascularization, Pathologic / Q000201:enzymology*; D024501:Nonmuscle Myosin Type IIB; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D042442:Vascular Endothelial Growth Factors
chemical_list: D016228:Endothelial Growth Factors; D016326:Extracellular Matrix Proteins; D008024:Ligands; D008222:Lymphokines; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000072483:Placenta Growth Factor; C501162:FLT1 protein, human; C501163:Flt1 protein, mouse; D011505:Protein-Tyrosine Kinases; D040281:Vascular Endothelial Growth Factor Receptor-1; D024501:Nonmuscle Myosin Type IIB; C103815:nonmuscle myosin type IIB heavy chain; D018995:Myosin Heavy Chains