Neuropilin-1 on hematopoietic cells as a source of vascular development.
Neuropilin-1 (NP-1) is a receptor for vascular endothelial growth factor-165 (VEGF165) and acts as a coreceptor that enhances the function of VEGF165 through VEGF receptor-2 (VEGFR-2). Studies using transgenic and knock-out mice of NP-1 indicated that this molecule is important for vascular development as well as neuronal development. We recently reported that clustered soluble NP-1 phosphorylates VEGFR-2 on endothelial cells with a low dose of VEGF165 and rescues the defective vascularity of the NP-1-/- embryo in vitro and in vivo. Here we show that NP-1 is expressed by CD45+ hematopoietic cells in the fetal liver, can bind VEGF165, and phosphorylates VEGFR-2 on endothelial cells. CD45+NP-1+ cells rescued the defective vasculogenesis and angiogenesis in the NP-1-/- P-Sp (para-aortic splanchnopleural mesodermal region) culture, although CD45+NP-1- cells did not. Moreover, CD45+NP-1+ cells together with VEGF165 induced angiogenesis in an in vivo Matrigel assay and cornea neovascularization assay. The extracellular domain of NP-1 consists of "a," "b," and "c" domains, and it is known that the "a" and "c" domains are necessary for dimerization of NP-1. We found that both the "a" and "c" domains are essential for such rescue of defective vascularities in the NP-1 mutant. These results suggest that NP-1 enhances vasculogenesis and angiogenesis exogenously and that dimerization of NP-1 is important for enhancing vascular development. In NP-1-/- embryos, vascular sprouting is impaired at the central nervous system (CNS) and pericardium where VEGF is not abundant, indicating that NP-1-expressing cells are required for normal vascular development.
Yamada
Yoshihiro
Y
Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine, Tokyo, Japan.
Oike
Yuichi
Y
Ogawa
Hisao
H
Ito
Yasuhiro
Y
Fujisawa
Hajime
H
Suda
Toshio
T
Takakura
Nobuyuki
N
D000818:Animals; D016175:B-Lymphocyte Subsets / Q000378:metabolism; D001808:Blood Vessels / Q000196:embryology; D019070:Cell Lineage; D003094:Collagen; D003315:Cornea / Q000098:blood supply; D019281:Dimerization; D004338:Drug Combinations; D016228:Endothelial Growth Factors / Q000378:metabolism; D004730:Endothelium, Vascular / Q000196:embryology*; D005838:Genotype; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007739:L Cells; D007797:Laminin; D008099:Liver / Q000166:cytology / Q000196:embryology; D008222:Lymphokines / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000235:genetics; D039942:Neuropilin-1 / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D011509:Proteoglycans; D011993:Recombinant Fusion Proteins / Q000502:physiology; D040121:Semaphorin-3A / Q000235:genetics / Q000502:physiology; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D042442:Vascular Endothelial Growth Factors
D004338:Drug Combinations; D016228:Endothelial Growth Factors; D007141:Immunoglobulin Fc Fragments; D036341:Intercellular Signaling Peptides and Proteins; D007797:Laminin; D008222:Lymphokines; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011509:Proteoglycans; D011993:Recombinant Fusion Proteins; D040121:Semaphorin-3A; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C059485:matrigel; D039942:Neuropilin-1; D003094:Collagen; D040301:Vascular Endothelial Growth Factor Receptor-2