title: Neurons limit angiogenesis by titrating VEGF in retina.
abstract: Vascular and nervous systems, two major networks in mammalian bodies, show a high degree of anatomical parallelism and functional crosstalk. During development, neurons guide and attract blood vessels, and consequently this parallelism is established. Here, we identified a noncanonical neurovascular interaction in eye development and disease. VEGFR2, a critical endothelial receptor for VEGF, was more abundantly expressed in retinal neurons than in endothelial cells, including endothelial tip cells. Genetic deletion of VEGFR2 in neurons caused misdirected angiogenesis toward neurons, resulting in abnormally increased vascular density around neurons. Further genetic experiments revealed that this misdirected angiogenesis was attributable to an excessive amount of VEGF protein around neurons caused by insufficient engulfment of VEGF by VEGFR2-deficient neurons. Moreover, absence of neuronal VEGFR2 caused misdirected regenerative angiogenesis in ischemic retinopathy. Thus, this study revealed neurovascular crosstalk and unprecedented cellular regulation of VEGF: retinal neurons titrate VEGF to limit neuronal vascularization. PAPERFLICK:
authors.affiliation: The Laboratory of Vascular Biology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; Department of Plastic Surgery, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Okabe
authors.affiliation: The Laboratory of Vascular Biology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Sakiko
authors.initials: S
authors.lastname: Kobayashi
authors.affiliation: The Laboratory of Vascular Biology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; Department of Surgery, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Department of Ophthalmology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Kurihara
authors.affiliation: The Laboratory of Vascular Biology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Ikue
authors.initials: I
authors.lastname: Tai-Nagara
authors.affiliation: Department of Orthopedic Surgery, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miyamoto
authors.affiliation: Laboratory of Stem Cell and Neuro-Vascular Biology, Genetics and Developmental Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 10/6C103, 10 Center Drive, Bethesda, MD 20892, USA.
authors.forename: Yoh-suke
authors.initials: YS
authors.lastname: Mukouyama
authors.affiliation: ERATO Sato Live Bio-Forecasting Project, Japan Science and Technology Agency, Kyoto 619-0288, Japan; Advanced Telecommunications Research Institute International, Kyoto 619-0288, Japan; Department of Biomedical Engineering, Ithaca, NY 14850, USA; Graduate School of Biological Sciences, Nara Institute of Science and Technology, Nara 630-0192, Japan; Centenary Institute, Sydney NSW 2050, Australia.
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Sato
authors.affiliation: Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Suda
authors.affiliation: Research Center for Animal Life Science, Shiga University of Medical Science, Seta, Tsukinowa-cho, Otsu, Shiga 520-2192, Japan.
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Ema
authors.affiliation: The Laboratory of Vascular Biology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Electronic address: ykubo33@a3.keio.jp.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kubota
mesh_terms: D000818:Animals; D004705:Endocytosis; D055879:Gene Knock-In Techniques; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D055495:Neurogenesis; D009474:Neurons / Q000378:metabolism*; D012160:Retina / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D042461:Vascular Endothelial Growth Factor A; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2