Selective induction of neuropilin-1 by vascular endothelial growth factor (VEGF): a mechanism contributing to VEGF-induced angiogenesis

Hideyasu Oh; Hitoshi Takagi; Atsushi Otani; Shinji Koyama; Seiji Kemmochi; Akiyoshi Uemura; Yoshihito Honda

doi:10.1073/pnas.012074399

Selective induction of neuropilin-1 by vascular endothelial growth factor (VEGF): a mechanism contributing to VEGF-induced angiogenesis

Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):383-8. doi: 10.1073/pnas.012074399. Epub 2001 Dec 26.

Authors

Hideyasu Oh¹, Hitoshi Takagi, Atsushi Otani, Shinji Koyama, Seiji Kemmochi, Akiyoshi Uemura, Yoshihito Honda

Affiliation

¹ Department of Ophthalmology and Visual Sciences, Graduate School of Medicine, Kyoto University, 54 Shogoinkawara-cho, Sakyo-ku, Kyoto 606-8507, Japan.

Abstract

Neuropilin (NRP) 1, previously identified as a neuronal receptor that mediates repulsive growth cone guidance, has been shown recently to function also in endothelial cells as an isoform-specific receptor for vascular endothelial growth factor (VEGF)(165) and as a coreceptor in vitro of VEGF receptor 2. However, its potential role in pathologic angiogenesis remains unknown. In the present study, we first show that VEGF selectively up-regulates NRP1 but not NRP2 via the VEGF receptor 2-dependent pathway. By NRP1 binding analysis, we showed that its induction by VEGF accompanies functional receptor expression. Endothelial proliferation stimulated by VEGF(165) was inhibited significantly by antibody perturbation of NRP1. In a murine model of VEGF-dependent angioproliferative retinopathy, intense NRP1 mRNA expression was observed in the newly formed vessels. Furthermore, selective NRP1 inhibition in this model suppressed neovascular formation substantially. These results suggest that VEGF cannot only activate endothelial cells directly but also can contribute to robust angiogenesis in vivo by a mechanism that involves up-regulation of its cognate receptor expression.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Aorta / cytology
Binding Sites
Blotting, Northern
Blotting, Western
Cattle
Cell Division
Cell Nucleus / metabolism
Cross-Linking Reagents / pharmacology
Dose-Response Relationship, Drug
Endothelial Growth Factors / metabolism*
Endothelium, Vascular / cytology*
Endothelium, Vascular / metabolism*
Immunoglobulin G / metabolism
Lymphokines / metabolism*
Mice
Neovascularization, Pathologic*
Nerve Tissue Proteins / biosynthesis*
Neuropilin-1
Oligonucleotide Array Sequence Analysis
Protein Binding
Protein Isoforms
RNA, Messenger / metabolism
Receptor Protein-Tyrosine Kinases / metabolism
Receptors, Growth Factor / metabolism
Receptors, Vascular Endothelial Growth Factor
Retina / cytology
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Time Factors
Up-Regulation
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factors

Substances

Cross-Linking Reagents
Endothelial Growth Factors
Immunoglobulin G
Lymphokines
Nerve Tissue Proteins
Protein Isoforms
RNA, Messenger
Receptors, Growth Factor
VEGFA protein, human
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factors
Neuropilin-1
Receptor Protein-Tyrosine Kinases
Receptors, Vascular Endothelial Growth Factor