Neurovascular crosstalk between interneurons and capillaries is required for vision
Yoshihiko Usui, … , Michael I. Dorrell, Martin Friedlander
Yoshihiko Usui, … , Michael I. Dorrell, Martin Friedlander
Published April 27, 2015
Citation Information: J Clin Invest. 2015;125(6):2335-2346. https://doi.org/10.1172/JCI80297.
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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 2

Vegfa deletion in amacrine and horizontal cells severely impairs intraretinal vasculature development.

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Vegfa deletion in amacrine and horizontal cells severely impairs intrar...
(A) In situ hybridization was performed on P12 Vegff/f or Ptf1a-Cre Vegff/f cryosectioned retinas with a Vegfa probe (counterstained with DAPI). (B) The intermediate plexus (green) is severely attenuated in P23 Ptf1a-Cre Vegff/f compared with controls. (C) Schematic of deep plexus development in a P10-staged mouse. Arrow illustrates the lateral growth of blood vessels in the OPL. (D) The number of branching events in the superficial and deep plexuses of P10 Vegff/f or Ptf1a-Cre Vegff/f retinas were counted and plotted (n = 4). (E) Schematic of vertical sprouting events from the deep plexus in P12 retinas. Arrow illustrates the direction of vascular sprouting from the deep plexus to the IPL. (F) There are no differences in the numbers of ascending vertical sprouts of Ptf1a-Cre Vegff/f in flat-mounted retinas compared with controls (Vegff/f) (n = 4). (G) Schematic of intermediate plexus development at P15. Arrow illustrates the lateral growth of blood vessels in the IPL. (H–J) GS-lectin–positive laterally expanding sprouts are fewer in number in P15 Ptf1a-Cre Vegff/f mice due to a reduced number of tip cells (I; arrows) and filopodia (J; arrowheads) (n = 4–5). (K) The number of branching points in the intermediate plexus were counted, quantified, and plotted at P12, P15, P23, and P60 (n = 4–6). *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, B, and H); 40 μm (I and J).