Editors' ChoiceDevelopmental Biology

Neurons Halt Angiogenesis

Sci. Signal.  11 Nov 2014:
Vol. 7, Issue 351, pp. ec315
DOI: 10.1126/scisignal.aaa2542

Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis. The distribution and activity of VEGF, which typically promotes angiogenic growth and vessel branching, is modulated by multiple mechanisms, including RNA splicing, interactions with the extracellular matrix, processing by proteases, and sequestration by soluble decoy receptors. Furthermore, the composition and abundance of receptors on VEGF-receiving cells influence the cellular response (see Domigan and Iruela-Arispe). During development of the retina in rodents, vascularization occurs on the inner surface but does not penetrate the neuronal layers. Okabe et al. found that the VEGF receptor VEGFR2 was more abundant in neuronal cells than in endothelial cells in developing mouse retinae. Neuronal-specific knockout of Vegfr2 in retinae of mice (Vegfr2Δneuro mice) did not affect neuronal development, but caused vessels to branch vertically into the neuronal layers. VEGF was endocytosed and degraded in retinal neurons of wild-type mice, but not Vegfr2Δneuro mice. Compared to wild-type mice, the abundance of extracellular VEGF was increased in Vegfr2Δneuro mice and in mice with neuronal-specific knockout of genes encoding proteins important for endocytosis (Dnm1;Dnm2Δneuro mice). Moreover, neuronal-specific knockout of Vegfa prevented vertical branching of vessels into the neuronal layers of retinae of Vegfr2Δneuro and Dnm1;Dnm2Δneuro mice. Thus, neurons bind and sequester VEGF and thereby, help to refine the spatiotemporal distribution of VEGF that guides angiogenic branching in the developing retina.

K. Okabe, S. Kobayashi, T. Yamada, T. Kurihara, I. Tai-Nagara, T. Miyamoto, Y. -s. Mukouyama, T. N. Sato, T. Suda, M. Ema, Y. Kubota, Neurons limit angiogenesis by titrating VEGF in retina. Cell 159, 584–596 (2014). [Online Journal]

C. K. Domigan, M. L. Iruela-Arispe, Stealing VEGF from thy neighbor. Cell 159, 473–474 (2014). [Online Journal]