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Blood, 1 December 2000, Vol. 96, No. 12, pp. 3793-3800
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
VEGF-C signaling pathways through VEGFR-2 and VEGFR-3 in
vasculoangiogenesis and hematopoiesis
Koichi Hamada,
Yuichi Oike,
Nobuyuki Takakura,
Yasuhiro Ito,
Lotta Jussila,
Daniel J. Dumont,
Kari Alitalo, and
Toshio Suda
From the Department of Cell Differentiation, Institute
of Molecular Embryology and Genetics, Kumamoto University, Japan;
Molecular/Cancer Biology Laboratory, Haartman Institute, PL21,
University of Helsinki, Helsinki, Finland; and the Department of
Medical Biophysics, University of Toronto, Ontario, Canada.
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.
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