COORDINATE EXPRESSION OF VASCULAR ENDOTHELIAL GROWTH-FACTOR RECEPTOR-1 (FLT-1) AND ITS LIGAND SUGGESTS A PARACRINE REGULATION OF MURINE VASCULAR DEVELOPMENT

Vascular endothelial growth factor (VEGF) is a candidate regulator of blood vessel growth during embryonic development and in tumors. To eva luate the role of VEGF receptor-1/flt-1 (VEGFR1/flt-1) in the developm ent of the vascular system, we have characterized the murine homolog o f the human flt-1 gene and have analyzed its expression pattern during mouse embryogenesis. Receptor binding studies using transfected COS c ells revealed that the murine flt-1 gene encodes a high affinity recep tor for VEGF. The apparent K-d for VEGF binding, as determined by Scat chard analysis, was 114 pM, demonstrating that VEGFRi/flt-1 has a high er affinity to VEGF than VEGF receptor-2/flk-1 (VEGFR2/flk-1). By in s itu hybridization, VEGFRi/flt-1 was detected in the yolk sac mesoderm already at the early stages of vascular development, while the recepto r ligand was expressed in the entire endoderm of 7.5-day mouse embryos . A comparison with VEGFR2/flk-1 showed that the two receptors shared a common expression domain in the yolk sac mesoderm, but were expresse d at different sites in the ectoplacental cone. The differential expre ssion of the two VEGF receptors persisted in the developing placenta, where VEGFR1/flt-1 mRNA was detected in the spongiotrophoblast layer, whereas VECFR2/flk-1 transcripts were present in the labyrinthine laye r which is the site of VEGF expression. In the embryo proper, VEGFR1/f lt-1 mRNA was specifically localized in blood vessels and capillaries of the developing organs, closely resembling the pattern of VEGFR2/flk -1 transcript distribution. In the developing brain, the expression of VEGF receptors in the perineural capillary plexus and in capillary sp routs which have invaded the neuroectoderm correlated with endothelial cell proliferation and brain angiogenesis. The data are consistent wi th the hypothesis that VEGF and its receptors have an important functi on both in the differentiation of the endothelial lineage and in the n eovascularization of developing organs, and act in a paracrine fashion . (C) 1995 Wiley-Liss, Inc.