Neuropilin-1 in regulation of VEGF-induced activation of p38MAPK and endothelial cell organization.
Vascular endothelial growth factor (VEGF)-A regulates vascular development and angiogenesis. VEGF isoforms differ in ability to bind coreceptors heparan sulfate (HS) and neuropilin-1 (NRP1). We used VEGF-A165 (which binds HS and NRP1), VEGF-A121 (binds neither HS nor NRP1), and parapoxvirus VEGF-E-NZ2 (binds NRP1 but not HS) to investigate the role of NRP1 in organization of endothelial cells into vascular structures. All 3 ligands induced similar level of VEGFR-2 tyrosine phosphorylation in the presence of NRP1. In contrast, sprouting angiogenesis in differentiating embryonic stem cells (embryoid bodies), formation of branching pericyte-embedded vessels in subcutaneous matrigel plugs, and sprouting of intersegmental vessels in developing zebrafish were induced by VEGF-A165 and VEGF-E-NZ2 but not by VEGF-A121. Analyses of recombinant factors with NRP1-binding gain- and loss-of-function properties supported the conclusion that NRP1 is critical for VEGF-induced sprouting and branching of endothelial cells. Signal transduction antibody arrays implicated NRP1 in VEGF-induced activation of p38MAPK. Inclusion of the p38MAPK inhibitor SB203580 in VEGF-A165-containing matrigel plugs led to attenuated angiogenesis and poor association with pericytes. Our data strongly indicate that the ability of VEGF ligands to bind NRP1 influences p38MAPK activation, and formation of functional, pericyte-associated vessels.
Kawamura
Harukiyo
H
Rudbeck Laboratory, Department of Genetics and Pathology, Uppsala, University, Uppsala, Sweden.
Li
Xiujuan
X
Goishi
Katsutoshi
K
van Meeteren
Laurens A
LA
Jakobsson
Lars
L
Cébe-Suarez
Stéphanie
S
Shimizu
Akio
A
Edholm
Dan
D
Ballmer-Hofer
Kurt
K
Kjellén
Lena
L
Klagsbrun
Michael
M
Claesson-Welsh
Lena
L
D000818:Animals; D030801:Animals, Genetically Modified; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008024:Ligands; D051379:Mice; D008954:Models, Biological; D018919:Neovascularization, Physiologic; D039942:Neuropilin-1 / Q000235:genetics / Q000378:metabolism*; D020286:Pericytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013552:Swine; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D015027:Zebrafish; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D008024:Ligands; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D048051:p38 Mitogen-Activated Protein Kinases