VEGF-C signaling pathways through VEGFR-2 and VEGFR-3 in vasculoangiogenesis and hematopoiesis.
Signaling by vascular endothelial growth factors (VEGFs) through VEGF receptors (VEGFRs) plays important roles in vascular development and hematopoiesis. The authors analyzed the function of VEGF-C signaling through both VEGFR-2 and VEGFR-3 in vasculoangiogenesis and hematopoiesis using a coculture of para-aortic splanchnopleural mesoderm (P-Sp) explants from mouse embryos with stromal cells (OP9). Vasculogenesis and angiogenesis were evaluated by the extent of vascular bed and network formation, respectively. Addition of VEGF-C to the P-Sp culture enhanced vascular bed formation and suppressed definitive hematopoiesis. Both vascular bed and network formations were completely suppressed by addition of soluble VEGFR-1-Fc competitor protein. Formation of vascular beds but not networks could be rescued by VEGF-C in the presence of the competitor, while both were rescued by VEGF-A. VEGFR-3-deficient embryos show the abnormal vasculature and severe anemia. Consistent with these in vivo findings, vascular bed formation in the P-Sp from the VEGFR-3-deficient embryos was enhanced to that in wild-type or heterozygous embryos, and hematopoiesis was severely suppressed. When VEGFR-3-Fc chimeric protein was added to trap endogenous VEGF-C in the P-Sp culture of the VEGFR-3-deficient embryos, vascular bed formation was suppressed and hematopoiesis was partially rescued. These results demonstrate that because VEGF-C signaling through VEGFR-2 works synergistically with VEGF-A, the binding of VEGF-C to VEGFR-3 consequently regulates VEGFR-2 signaling. In VEGFR-3-deficient embryos, an excess of VEGF-C signals through VEGFR-2 induced the disturbance of vasculogenesis and hematopoiesis during embryogenesis. This indicates that elaborated control through VEGFR-3 signaling is critical in vasculoangiogenesis and hematopoiesis. (Blood. 2000;96:3793-3800)
Hamada
K
K
Department of Cell Differentiation, Institute of Molecular Embryology and Genetics, Kumamoto University, Japan.
Oike
Y
Y
Takakura
N
N
Ito
Y
Y
Jussila
L
L
Dumont
D J
DJ
Alitalo
K
K
Suda
T
T
D000818:Animals; D001808:Blood Vessels / Q000002:abnormalities / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D018920:Coculture Techniques; D004622:Embryo, Mammalian / Q000098:blood supply / Q000737:chemistry; D016228:Endothelial Growth Factors / Q000494:pharmacology / Q000502:physiology*; D006410:Hematopoiesis / Q000187:drug effects*; D006801:Humans; D007150:Immunohistochemistry; D008648:Mesoderm / Q000737:chemistry / Q000166:cytology; D051379:Mice; D008817:Mice, Mutant Strains; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology; D017978:Receptors, Growth Factor / Q000378:metabolism / Q000502:physiology*; D040262:Receptors, Vascular Endothelial Growth Factor; D015398:Signal Transduction / Q000187:drug effects; D013152:Splanchnic Circulation; D017154:Stromal Cells / Q000737:chemistry / Q000166:cytology; D042582:Vascular Endothelial Growth Factor C; D040321:Vascular Endothelial Growth Factor Receptor-3; D015017:Yolk Sac / Q000098:blood supply
D016228:Endothelial Growth Factors; D017978:Receptors, Growth Factor; D042582:Vascular Endothelial Growth Factor C; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D040321:Vascular Endothelial Growth Factor Receptor-3