The vascular endothelial growth factor (VEGF) receptor Flt-1 (VEGFR-1) modulates Flk-1 (VEGFR-2) signaling during blood vessel formation.
Mice lacking the vascular endothelial growth factor (VEGF) receptor flt-1 (VEGFR-1) die from vascular overgrowth, caused primarily by aberrant endothelial cell division (Kearney JB, Ambler CA, Monaco KA, Johnson N, Rapoport RG, Bautch VL: Vascular endothelial growth factor receptor Flt-1 negatively regulates developmental blood vessel formation by modulating endothelial cell division. Blood 2002, 99:2397-2407). Because a second high-affinity VEGF receptor, flk-1, produces a positive endothelial proliferation signal, it was logical to ask whether flt-1 affects developmental blood vessel formation by modulating signaling through flk-1. Differentiated embryonic stem cell cultures lacking flt-1 (flt-1-/-) had increased flk-1 tyrosine phosphorylation, indicating that flk-1 signaling is up-regulated in the mutant background. The selective flk-1 inhibitor SU5416 partially rescued the flt-1-/- mutant phenotype, and this rescue was accompanied by a decrease in the relative amount of flk-1 tyrosine phosphorylation. Thus reduced flk-1 signal transduction can partially compensate for the lack of flt-1. The flt-1-/- mutant phenotype was also partially rescued by Flt-1/Fc, a truncated flt-1 that binds and sequesters the VEGF ligand. Taken together, these data show that down-regulation of flk-1 signaling by two different strategies partially rescues the developmental vascular overgrowth seen in the absence of flt-1, and they support a model whereby flt-1 modulates the flk-1 signal at an early point in the pathway.
Roberts
David M
DM
Program in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill 27599, USA.
Kearney
Joseph B
JB
Johnson
Jennifer H
JH
Rosenberg
Michael P
MP
Kumar
Rakesh
R
Bautch
Victoria L
VL
D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D007211:Indoles / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D009154:Mutation; D018919:Neovascularization, Physiologic; D010641:Phenotype; D010766:Phosphorylation; D011758:Pyrroles / Q000494:pharmacology; D015398:Signal Transduction; D013997:Time Factors; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
D007211:Indoles; D008024:Ligands; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D014443:Tyrosine; C116890:Semaxinib; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2