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Blood, 15 March 2001, Vol. 97, No. 6, pp. 1671-1678
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Exogenous clustered neuropilin 1 enhances vasculogenesis and
angiogenesis
Yoshihiro Yamada,
Nobuyuki Takakura,
Hirofumi Yasue,
Hisao Ogawa,
Hajime Fujisawa, and
Toshio Suda
From the Department of Cell Differentiation, Institute
of Molecular Embryology and Genetics, and the Department of
Cardiovascular Medicine, Kumamoto University School of Medicine,
Kumamoto, Japan; and the Group of Developmental Neurobiology, Division
of Biological Science, Nagoya University Graduate School of Science,
Japan.
Neuropilin 1 (NP-1) is a receptor for vascular endothelial growth
factor (VEGF) 165 (VEGF165) and acts as a coreceptor that enhances VEGF165 function through tyrosine kinase VEGF
receptor 2 (VEGFR-2). Transgenic overexpression of np-1
results in an excess of capillaries and blood vessels and a malformed
heart. Thus, NP-1 may have a key role in vascular development. However,
how NP-1 regulates vascular development is not well understood. This study demonstrates how NP-1 can regulate vasculogenesis and
angiogenesis in vitro and in vivo. In homozygous np-1
mutant (np-1 /) murine embryos, vascular
sprouting was impaired in the central nervous system and pericardium.
Para-aortic splanchnopleural mesoderm (P-Sp) explants from
np-1/ mice also had vascular defects in
vitro. A monomer of soluble NP-1 (NP-1 tagged with Flag epitope)
inhibited vascular development in cultured wild-type P-Sp explants by
sequestering VEGF165. In contrast, a dimer of soluble NP-1
(NP-1 fused with the Fc part of human IgG) enhanced vascular
development in cultured wild-type P-Sp explants. Moreover, the NP-1-Fc
rescued the defective vascular development in cultured
np-1/ P-Sp explants. A low dose of VEGF
alone did not promote phosphorylation of VEGFR-2 on endothelial
cells from np-1/ embryos, but
simultaneous addition of a low dose of VEGF and NP-1-Fc phosphorylated
VEGFR-2 significantly. Moreover, NP-1-Fc rescued the defective
vascularity of np-1/ embryos in vivo. These
results suggest that a dimer form of soluble NP-1 delivers
VEGF165 to VEGFR-2-positive endothelial cells and promotes angiogenesis.
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