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BCL6B Contributes to Ocular Vascular Diseases via Notch Signal Silencing
Miruto Tanaka1, Shinsuke Nakamura1, Tomohisa Sakaue2,3
1Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Japan (M.T., S.N., T.Y., A.N., H.Y., M.S., H.H.).
Insights
BCL6B protein promotes retinal edema and neovascularization by activating VEGF signaling. Inhibiting BCL6B reduced these conditions, suggesting it as a therapeutic target for ocular vascular diseases.
Area of Science:
- Ophthalmology
- Molecular Biology
- Cell Biology
Background:
- Endothelial cell activation is regulated by vascular endothelial cell growth factor (VEGF) and Notch signaling.
- VEGF promotes neovascularization and blood vessel destabilization, contributing to sight-threatening ocular vascular disorders.
- BCL6B (B-cell CLL/lymphoma 6 member B protein) is implicated in retinal edema and neovascularization.
Purpose of the Study:
- To investigate the pathophysiological role of BCL6B in ocular vascular conditions.
- To determine BCL6B's involvement in retinal edema and neovascularization.
- To evaluate BCL6B as a potential therapeutic target for ocular vascular diseases.
Main Methods:
- Investigated BCL6B in cellular and animal models of retinal vein occlusion and choroidal neovascularization.
- Utilized in vitro human retinal microvascular endothelial cells treated with VEGF.
- Examined BCL6B knockout mice and cynomolgus monkeys treated with BCL6B-targeting small-interfering ribose nucleic acid.
Main Results:
- VEGF increased BCL6B expression in retinal endothelial cells.
- BCL6B deficiency activated Notch signaling and attenuated cord formation by blocking VEGF-VEGFR2 pathway.
- BCL6B inhibition reduced choroidal neovascularization and suppressed ocular edema in mice.
- BCL6B knockout abrogated proangiogenic cytokines and inner blood-retinal barrier breakdown via Notch activation.
- Müller cell activation, a VEGF source, was diminished in BCL6B-knockout retinas.
Conclusions:
- BCL6B plays a pivotal role in ocular neovascularization and edema.
- Targeting BCL6B offers a potential therapeutic strategy for ocular vascular diseases.
- BCL6B inhibition modulates VEGF and Notch signaling pathways in the retina.
Background:
Endothelial cell activation is tightly controlled by the balance between VEGF (vascular endothelial cell growth factor) and Notch signaling pathway. VEGF destabilizes blood vessels and promotes neovascularization, which are common features of sight-threatening ocular vascular disorders. Here, we show that BCL6B (B-cell CLL/lymphoma 6 member B protein), also known as BAZF, ZBTB28, and ZNF62, plays a pivotal role in the development of retinal edema and neovascularization.
Methods:
The pathophysiological physiological role of BCL6B was investigated in cellular and animal models mimicking 2 pathological conditions: retinal vein occlusion and choroidal neovascularization. An in vitro experimental system was used in which human retinal microvascular endothelial cells were supplemented with VEGF. Choroidal neovascularization cynomolgus monkey model was generated to investigate the involvement of BCL6B in the pathogenesis. Mice lacking BCL6B or treated with BCL6B-targeting small-interfering ribose nucleic acid were examined for histological and molecular phenotypes.
Results:
In retinal endothelial cells, the BCL6B expression level was increased by VEGF. BCL6B-deficient endothelial cells showed Notch signal activation and attenuated cord formation via blockage of the VEGF-VEGFR2 signaling pathway. Optical coherence tomography images showed that choroidal neovascularization lesions were decreased by BCL6B-targeting small-interfering ribose nucleic acid. Although BCL6B mRNA expression was significantly increased in the retina, BCL6B-targeting small-interfering ribose nucleic acid suppressed ocular edema in the neuroretina. The increase in proangiogenic cytokines and breakdown of the inner blood-retinal barrier were abrogated in BCL6B knockout (KO) mice via Notch transcriptional activation by CBF1 (C promotor-binding factor 1) and its activator, the NICD (notch intracellular domain). Immunostaining showed that Müller cell activation, a source of VEGF, was diminished in BCL6B-KO retinas.
Conclusions:
These data indicate that BCL6B may be a novel therapeutic target for ocular vascular diseases characterized by ocular neovascularization and edema.
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