Involvement of Flt-1 tyrosine kinase (vascular endothelial growth factor receptor-1) in pathological angiogenesis

Vascular endothelial growth factor (VEGF) and its two receptors, Fms-like t yrosine kinase 1 (Flt-1) (VEGFR-1) and KDR/FIk-1 (VEGFR-2), have been demon strated 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 activi ty, in-fold higher affinity to VEGF, whereas much weaker tyrosine kinase ac tivity compared with KDR, Recently, we and others have shown that Flt-1 has a negative regulatory function for physiological angiogenesis in the embry o, possibly with its strong VEGF-trapping activity, However, it is still op en to question whether the tyrosine kinase of Flt-1 has any positive role i n angiogenesis at adult stages, In this study, we examined whether Flt-1 co uld be a positive signal transducer under certain pathological conditions, such as angiogenesis with tumors overexpressing a Flt-1-specific, VEGF-rela ted 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 t han in Flt-1 tyrosine kinase-deficient mice. On the other hand, the same ca rcinoma cells overexpressing VEGF showed no clear difference in the tumor g rowth 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 ne gative manner in different biological conditions.