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Rb1/Rbl1/Vhl loss induces mouse subretinal angiomatous proliferation and hemangioblastoma
Ran Wei, … , Rod Bremner, Danian Chen
Ran Wei, … , Rod Bremner, Danian Chen
Published October 15, 2019
Citation Information: JCI Insight. 2019;4(22):e127889. https://doi.org/10.1172/jci.insight.127889.
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Research Article Angiogenesis Ophthalmology

Rb1/Rbl1/Vhl loss induces mouse subretinal angiomatous proliferation and hemangioblastoma

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Abstract

Von Hippel–Lindau (Vhl) protein inhibits hypoxia-inducible factor (Hif), yet its deletion in murine retina does not cause the extensive angiogenesis expected with Hif induction. The mechanism is unclear. Here we show that retinoblastoma tumor suppressor (Rb1) constrains expression of Hif target genes in the Vhl–/– retina. Deleting Rb1 induced extensive retinal neovascularization and autophagic ablation of photoreceptors in the Vhl–/– retina. RNA-sequencing, ChIP, and reporter assays showed Rb1 recruitment to and repression of certain Hif target genes. Activating Rb1 by deleting cyclin D1 induced a partial defect in the retinal superficial vascular plexus. Unexpectedly, removing Vhl suppressed retinoblastoma formation in murine Rb1/Rbl1–deficient retina but generated subretinal vascular growths resembling retinal angiomatous proliferation (RAP) and retinal capillary hemangioblastoma (RCH). Most stromal cells in the RAP/RCH–like lesions were Sox9+, suggesting a Müller glia origin, and expressed Lgals3, a marker of human brain hemangioblastoma. Thus, the Rb family limit Hif target gene expression in the Vhl–/– retina, and removing this inhibitory signal generates new models for RAP and RCH.

Authors

Ran Wei, Xiang Ren, Hongyu Kong, Zhongping Lv, Yongjiang Chen, Yunjing Tang, Yujiao Wang, Lirong Xiao, Tao Yu, Sabiha Hacibekiroglu, Chen Liang, Andras Nagy, Rod Bremner, Danian Chen

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Figure 1

Retinal neovascularization in the Rb1/Vhl–DKO and Rb1+/– Vhl–/– retinas.

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Retinal neovascularization in the Rb1/Vhl–DKO and Rb1+/– Vhl–/– retinas....
(A) IB4 staining of P18 whole-mount retinas of indicated genotypes. Selected areas are blown up to show the vascular density. (B) IB4 (green) and DAPI (blue) staining of P18 retinal sections of indicated genotypes. (C) Quantification of vessel branching points per fields of view (FOV) by AngioTool software. (D) IB4 staining of the P8 Rb1/Vhl–DKO whole-mount retina. The hyaloid vessels and DVP layers were shown. Arrowheads indicate that new blood vessels link to hyaloid vessels. Arrows indicate new blood vessels link to retinal DVP. (E) IB4 staining of the P14 Rb1/Vhl–DKO whole-mount retina. Blowup shows the grape-like clusters of endothelial cells. (F) IB4 (green) and DAPI (blue) staining of the P14 Rb1/Vhl–DKO retinal sections shows the grape-like clusters of endothelial cells. (G and H) FFA images of the P14 Rb1/Vhl–DKO eye to show delayed regression of hyaloid vessels (G) and retinal vascular leakages (H, arrows). (I) Retinal whole-mount of P18 Rb1/Vhl–DKO mice after retroorbital injection of FITC-dextran, to show retinal vascular leakages. (J) IB4 staining of P730 (2 years old) Rb1/Vhl–DKO whole-mount retina. Error bars represent SD of measurements from 3 retinas (n = 3), and asterisks indicate significant differences between WT and indicated genotypes (*P < 0.05, **P < 0.01, 1-way ANOVA followed by Bonferroni’s correction). The dotted lines in A, D, E, I, and J indicate the boundary between no Cre expression (in the center) and α-Cre expression areas (in the periphery). ONL: outer nuclear layer; INL: inner nuclear layer; IVP: intermediate vascular plexus; GCL: ganglion cell layer. Scale bars: 50 μm (F), 100 μm (B), and 200 μm (A, D, E, I, and J).

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