Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium

Abstract

The vascular endothelial growth factor (VEGF) and its high-affinity binding receptors, the tyrosine kinases Flt-1 and Flk-1, are thought to be important for the development of embryonic vasculature. Here we report that Flt-1 is essential for the organization of embryonic vasculature, but is not essential for endothelial cell differentiation. Mouse embryos homozygous for a targeted mutation in the flt-1 locus, flt-1lcz, formed endothelial cells in both embryonic and extra-embryonic regions, but assembled these cells into abnormal vascular channels and died in utero at mid-somite stages. At earlier stages, the blood islands of flt-1lcz homozygotes were abnormal, with angioblasts in the interior as well as on the periphery. We suggest that the Flt-1 signalling pathway may regulate normal endothelial cell-cell or cell-matrix interactions during vascular development.

Vasculogenic mimicry by bone marrow macrophages in patients with multiple myeloma

“…VEGFR-1 mediates macrophage chemotaxis (Barleon et al, 1996) and the organization of the embryo vasculature by vasculogenesis (Fong et al, 1995), but not the definitive vessel assembly, which is closely dependent on VEGFR-2, a specific EC differentiation marker (Shalaby et al, 1999). The bFGF/ FGFRs system is mandatory for vasculogenesis, since it induces angioblasts to differentiate and assemble into initial vascular patterns (Gendron et al, 1996).…”

Roles of two VEGF receptors, Flt-1 and KDR, in the signal transduction of VEGF effects in human vascular endothelial cells

“…Indeed, KDR is shown to be a key marker de®ning hematopoietic stem cells in human postnatal hematopoietic tissue (Ziegler et al, 1999). In contrast, Flt-1 knockout mice, which also die around E8.5, have abundant ECs, which do not assemble in functional vessels (Fong et al, 1995). In spite of these observations, properties of KDR/Flk-1 and Flt-1 in normally di erentiated ECs are controversial.…”

The Tek/Tie2 receptor signals through a novel Dok-related docking protein, Dok-R

“…Tie remains an orphan receptor while the ligands for Tek have recently been identi®ed as Angiopoietin-1 and -2 Maisonpierre et al, 1997). Targeted null mutations in all of these receptors result in embryonic lethality (Shalaby et al, 1995;Fong et al, 1995;Dumont et al, in prep. ;Dumont et al, 1994;Sato et al, 1995;Puri et al, 1995), and the lethal phenotype is distinct for each receptor.…”