Neurons limit angiogenesis by titrating VEGF in retina

Keisuke Okabe, Sakiko Kobayashi, Toru Yamada, Toshihide Kurihara, Ikue Tai-Nagara, Takeshi Miyamoto, Yoh Suke Mukouyama, Thomas N. Sato, Toshio Suda, Masatsugu Ema, Yoshiaki Kubota

Research output: Contribution to journalArticlepeer-review

209 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)584-596
Number of pages13
Issue number3
Publication statusPublished - 2014 Oct 23

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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