Roles of HIFs and VEGF in angiogenesis in the retina and brain
Amir Rattner, … , John Williams, Jeremy Nathans
Amir Rattner, … , John Williams, Jeremy Nathans
Published August 12, 2019
Citation Information: J Clin Invest. 2019;129(9):3807-3820. https://doi.org/10.1172/JCI126655.
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Research Article Development Vascular biology

Roles of HIFs and VEGF in angiogenesis in the retina and brain

Abstract

Vascular development in the mammalian retina is a paradigm for CNS vascular development in general, and its study is revealing fundamental mechanisms that explain the efficacy of antiangiogenic therapies in retinal vascular disease. During development of the mammalian retina, hypoxic astrocytes are hypothesized to secrete VEGF, which attracts growing endothelial cells as they migrate radially from the optic disc. However, published tests of this model using astrocyte-specific deletion of Vegf in the developing mouse retina appear to contradict this theory. Here, we report that selectively eliminating Vegf in neonatal retinal astrocytes with a Gfap-Cre line that recombines with approximately 100% efficiency had no effect on proliferation or radial migration of astrocytes, but completely blocked radial migration of endothelial cells, strongly supporting the hypoxic astrocyte model. Using additional Cre driver lines, we found evidence for essential and partially redundant actions of retina-derived (paracrine) and astrocyte-derived (autocrine) VEGF in controlling astrocyte proliferation and migration. We also extended previous studies by showing that HIF-1α in retinal neurons and HIF-2α in Müller glia play distinct roles in retinal vascular development and disease, adding to a growing body of data that point to the specialization of these 2 hypoxia-sensing transcription factors.

Authors

Amir Rattner, John Williams, Jeremy Nathans

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Figure 6

Persistent hyaloid vasculature in eyes without astrocyte-derived VEGF.

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Persistent hyaloid vasculature in eyes without astrocyte-derived VEGF. (...
(A–D) The left column shows frozen eye sections stained with GSL at P14. The hyaloid vasculature is retained in Gfap-Cre Vegffl/fl eyes (arrows in left panel of B) and regresses in Gfap-Cre Vegffl/+, Six3-Cre Vegffl/+, and Six3-Cre Vegffl/fl eyes (arrowheads in left panels of A, C, and D). The right 2 columns show semithin plastic sections stained with toluidine blue (middle and far-right panels of A–D). In Gfap-Cre Vegffl/fl eyes, there is hyperproliferation of astrocytes on the vitreal face of the retina (red arrowheads in middle panel of B) and retention of hyaloid vessels near the lens (retrolental vessels; arrows in far-right panel of B). In the 3 other genotypes, the retrolental vasculature has almost completely regressed (arrowheads in far-right panels of A, C, and D). Representative frozen sections are shown from experiments with a total of 4 eyes per genotype, and representative plastic sections are shown from experiments with a total of 2 eyes per genotype. Scale bars: 500 μm (left panels of A–D) and 100 μm (middle and far-right panels of A–D).