Antibody-Mediated Inhibition of Tspan12 Ameliorates Vasoproliferative Retinopathy Through Suppression of β-Catenin Signaling

Bucher, Felicitas; Zhang, Ding; Aguilar, Edith; Sakimoto, Susumu; Diaz-Aguilar, Sophia; Rosenfeld, Mauricio; Zha, Zhao; Zhang, Hongkai; Friedlander, Martin; Yea, Kyungmoo

doi:10.1161/circulationaha.116.025604

Cited by 21 publications

(30 citation statements)

References 48 publications

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“…Together, these studies emphasize the importance of norrin signaling through FZD4 and TSPAN12 coreceptor. Since there is ongoing research examining the use of antibodies against TSPAN12 in angiogenesis (47,48), it is important to understand the specific role of norrin receptor molecules in retinal barrier biology.…”

Section: Discussionmentioning

confidence: 99%

Norrin restores blood-retinal barrier properties after vascular endothelial growth factor–induced permeability

Díaz-Coránguez

Lin

Liebner

et al. 2020

Journal of Biological Chemistry

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Vascular endothelial growth factor (VEGF) contributes to blood-retinal barrier (BRB) dysfunction in several blinding eye diseases, including diabetic retinopathy. Signaling via the secreted protein norrin through the frizzled class receptor 4 (FZD4)/LDL receptor–related protein 5–6 (LRP5–6)/tetraspanin 12 (TSPAN12) receptor complex is required for developmental vascularization and BRB formation. Here, we tested the hypothesis that norrin restores BRB properties after VEGF-induced vascular permeability in diabetic rats or in animals intravitreally injected with cytokines. Intravitreal co-injection of norrin with VEGF completely ablated VEGF-induced BRB permeability to Evans Blue-albumin. Likewise, 5-month diabetic rats exhibited increased permeability of FITC-albumin, and a single norrin injection restored BRB properties. These results were corroborated in vitro, where co-stimulation of norrin with VEGF or stimulation of norrin after VEGF exposure restored barrier properties, indicated by electrical resistance or 70-kDa RITC-dextran permeability in primary endothelial cell culture. Interestingly, VEGF promoted norrin signaling by increasing the FZD4 co-receptor TSPAN12 at cell membranes in an MAPK/ERK kinase (MEK)/ERK-dependent manner. Norrin signaling through β-catenin was required for BRB restoration, but glycogen synthase kinase 3 α/β (GSK-3α/β) inhibition did not restore BRB properties. Moreover, levels of the tight junction protein claudin-5 were increased with norrin and VEGF or with VEGF alone, but both norrin and VEGF were required for enriched claudin-5 localization at the tight junction. These results suggest that VEGF simultaneously induces vascular permeability and promotes responsiveness to norrin. Norrin, in turn, restores tight junction complex organization and BRB properties in a β-catenin–dependent manner.

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Section: Discussionmentioning

confidence: 99%

Norrin restores blood-retinal barrier properties after vascular endothelial growth factor–induced permeability

Díaz-Coránguez

Lin

Liebner

et al. 2020

Journal of Biological Chemistry

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“…13,14 Analogously to the human eye, there is a need to precisely characterize the phenotype of animal models in order to understand the pathophysiology such that these models can reliably be used for comparative studies of the human eye and the development of novel molecular approaches preventing disease progression. [15][16][17] Multimodal imaging proved to be a valuable approach for the differentiation between different AMD types in the human eye. 4 Especially SD-OCT pushed diagnosis and has recently been combined with OCT angiography (OCTA) 18,19 in order to enable a better understanding of vascular patterns associated with neovascularizations on a capillary level in the human eye 20,21 but also in the rodent retina.…”

Section: Conclusion Longitudinal Multifunctional Oct Imaging Of Inmentioning

confidence: 99%

In Vivo Characterization of Spontaneous Retinal Neovascularization in the Mouse Eye by Multifunctional Optical Coherence Tomography

Augustin

Wechdorn

Pfeiffenberger

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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“…3,4 In DR, hyperglycemia gradually induces progressive alterations in the retinal microvasculature with a loss of pericyte coverage leading to areas of retinal nonperfusion. 10,11 Therefore, new therapeutic agents are needed for the effective treatment of vision-threatening NV. 5,6 With an improved understanding of the disorder from clinical examination and through the use of relevant animal models, it appears that ROP and DR are characterized by a biphasic process: phase I involves delayed physiologic retinal vascular development with a vasoregression and phase II involves vasoproliferation with development of abnormal vessels.…”

Section: Introductionmentioning

confidence: 99%

Therapies targeting Frizzled‐7/β‐catenin pathway prevent the development of pathological angiogenesis in an ischemic retinopathy model

et al. 2019

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Retinopathies remain major causes of visual impairment in diabetic patients and premature infants. Introduction of anti-angiogenic drugs targeting vascular endothelial growth factor (VEGF) has transformed therapy for these proliferative retinopathies.However, limitations associated with anti-VEGF medications require to unravel new pathways of vessel growth to identify potential drug targets. Here, we investigated the role of Wnt/Frizzled-7 (Fzd7) pathway in a mouse model of oxygen-induced retinopathy (OIR). Using transgenic mice, which enabled endothelium-specific and time-specific Fzd7 deletion, we demonstrated that Fzd7 controls both vaso-obliteration and neovascular phases (NV). Deletion of Fzd7 at P12, after the ischemic phase of OIR, prevented formation of aberrant neovessels into the vitreous by suppressing proliferation of endothelial cells (EC) in tufts. Next we validated in vitro two Frd7 blocking strategies: a monoclonal antibody (mAbFzd7) against Fzd7 and a soluble Fzd7 receptor (CRD). In vivo a single intravitreal microinjection of mAb-Fzd7 or CRD significantly attenuated retinal neovascularization (NV) in mice with OIR. Molecular analysis revealed that Fzd7 may act through the activation of Wnt/βcatenin and Jagged1 expression to control EC proliferation in extra-retinal neovessels. We identified Fzd7/β-catenin signaling as new regulator of pathological retinal NV. Fzd7 appears to be a potent pharmacological target to prevent or treat aberrant angiogenesis of ischemic retinopathies. K E Y W O R D S

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Antibody-Mediated Inhibition of Tspan12 Ameliorates Vasoproliferative Retinopathy Through Suppression of β-Catenin Signaling

Abstract: Tspan12/β-catenin signaling is critical for the progression of vasoproliferative disease. The newly developed anti-Tspan12 antibody has therapeutic effects in vasoproliferative retinopathy and can enhance the potency of existing anti- vascular endothelial growth factor agents.

Cited by 21 publications

References 48 publications

Norrin restores blood-retinal barrier properties after vascular endothelial growth factor–induced permeability

Norrin restores blood-retinal barrier properties after vascular endothelial growth factor–induced permeability

In Vivo Characterization of Spontaneous Retinal Neovascularization in the Mouse Eye by Multifunctional Optical Coherence Tomography

Therapies targeting Frizzled‐7/β‐catenin pathway prevent the development of pathological angiogenesis in an ischemic retinopathy model

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