Neurovascular crosstalk between interneurons and capillaries is required for vision
Yoshihiko Usui, Peter D. Westenskow, Toshihide Kurihara, Edith Aguilar, Susumu Sakimoto, Liliana P. Paris, Carli Wittgrove, Daniel Feitelberg, Mollie S.H. Friedlander, Stacey K. Moreno, Michael I. Dorrell, Martin Friedlander
Yoshihiko Usui, Peter D. Westenskow, Toshihide Kurihara, Edith Aguilar, Susumu Sakimoto, Liliana P. Paris, Carli Wittgrove, Daniel Feitelberg, Mollie S.H. Friedlander, Stacey K. Moreno, Michael I. Dorrell, Martin Friedlander
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Research Article Vascular biology

Neurovascular crosstalk between interneurons and capillaries is required for vision

Abstract

Functional interactions between neurons, vasculature, and glia within neurovascular units are critical for maintenance of the retina and other CNS tissues. For example, the architecture of the neurosensory retina is a highly organized structure with alternating layers of neurons and blood vessels that match the metabolic demand of neuronal activity with an appropriate supply of oxygen within perfused blood. Here, using murine genetic models and cell ablation strategies, we have demonstrated that a subset of retinal interneurons, the amacrine and horizontal cells, form neurovascular units with capillaries in 2 of the 3 retinal vascular plexuses. Moreover, we determined that these cells are required for generating and maintaining the intraretinal vasculature through precise regulation of hypoxia-inducible and proangiogenic factors, and that amacrine and horizontal cell dysfunction induces alterations to the intraretinal vasculature and substantial visual deficits. These findings demonstrate that specific retinal interneurons and the intraretinal vasculature are highly interdependent, and loss of either or both elicits profound effects on photoreceptor survival and function.

Authors

Yoshihiko Usui, Peter D. Westenskow, Toshihide Kurihara, Edith Aguilar, Susumu Sakimoto, Liliana P. Paris, Carli Wittgrove, Daniel Feitelberg, Mollie S.H. Friedlander, Stacey K. Moreno, Michael I. Dorrell, Martin Friedlander

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Figure 4

VHL/HIF-1α/VEGF signaling regulates angiogenesis in the intermediate plexus.

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VHL/HIF-1α/VEGF signaling regulates angiogenesis in the intermediate ple...
(A–F) Compared with control (A), combinatorial conditional KO strategies were employed to show that the loss of HIF-1α (B; quantified in H) but not HIF-2α (C; quantified in I) in amacrine and horizontal cells interferes with intermediate plexus development in haplosufficient P23 Vhl+/- mutants. (D–F) Homozygous deletion of P23 Vhl and Hif-1α (E) prevents the neovascularization observed in Vhl mutants (D and E; quantified in J), but deletion of Hif-2α elicits no effect (F; quantified in K) compared with controls (D). (G; quantified in L) Homozygous deletion of Vhl and Vegfa also rescues the Vhl neovascular phenotype. (All assays were performed in P23-staged mice; n = 4–6). (M) Relative mRNA expression values from qPCR gene-profiling analysis of 84 angiogenesis-related genes in Ptf1a-Cre Vhlf/f Vegff/f retinas at P12 compared with controls (harboring floxed alleles but no Cre); upregulated genes (P < 0.05 or fold change > 1.5 [marked by red dashed line]) are plotted (n = 4). *P < 0.05, **P < 0.01, ***P < 0.001; 2-tailed Student’s t tests. Error bars indicate mean ± SD. Scale bars: 50 μm (A–G).