Cell
Volume 159, Issue 3, 23 October 2014, Pages 584-596
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Article
Neurons Limit Angiogenesis by Titrating VEGF in Retina

https://doi.org/10.1016/j.cell.2014.09.025Get rights and content
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Highlights

  • Retinal neurons highly express VEGFR2 via a hemangioblast-specific enhancer, DMME

  • Loss of VEGFR2 in retinal neurons causes misdirected angiogenesis toward neurons

  • Deletion of neuronal VEGF normalizes vascular defects in neuronal VEGFR2 knockouts

  • Excessive VEGF due to poor engulfment by VEGFR2 null neurons misdirects angiogenesis

Summary

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.

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