Research Background and Overview of this study
Roughly 90% of the information that humans receive is said to come from vision, and with the rapid progress of advanced information technology in society as a whole, the importance of visual function is further increasing in our daily lives. In addition, the maintenance and improvement of visual function play an extremely important role in extending healthy life expectancy in a super-aging society. Some diseases, such as exudative age-related macular degeneration and retinal vein occlusion, cause visual field loss and vision loss when the small blood vessels in the eye become clogged or the vessel walls become brittle, causing blood components to leak out and form abnormal angiogenesis. Elucidation of the molecular mechanisms that maintain vascular health and establishment of treatments for such ocular diseases caused by vascular abnormalities will lead to an increase in healthy life expectancy.
Vascular endothelial growth factor (VEGF) has been identified as the protein responsible for vascular fragility and abnormal angiogenesis, and therapeutic strategies that regulate VEGF signaling are currently successful in clinical practice for ocular vascular pathologies. However, the pathogenesis and progression of ocular vascular lesions are very complex, and it has been reported that signals other than VEGF are also involved. The research group led by Gifu Pharmaceutical University has been focusing on an intracellular protein called BCL6B. They found that when BCL6B is increased in blood vessels in the eye, substances important for the maintenance of normal blood vessels are decreased, resulting in angiogenesis and edema, and that BCL6B siRNA, a nucleic acid medicine, that decreases the expression level of BCL6B suppresses pathological vascular symptoms. This discovery is the first to show that an intracellular substance that destabilizes blood vessels causes eye diseases, and the realization of a BCL6B-targeted therapy is expected to contribute to the "joy of seeing" for as many patients as possible.
Summary of Research Results
A research group led by Associate Professor Shinsuke Nakamura, Professor Masamitsu Shimazawa, and President Hideaki Hara of Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, in collaboration with Ehime University, Chiba University, and Carna Biosciences, Inc., has discovered that the molecule BCL6B is important for maintaining healthy eye vessels. The research results of this research were published in Arteriosclerosis, Thrombosis, and Vascular Biology on April 20, 2023. Figures 1-3 below are reproduced from the figures and graphical abstract in the paper with modifications.
The research group produced retinal vein occlusion model mice, and examined the expression site of BCL6B in the retina, and found that BCL6B is strongly expressed in the area where blood flow is interrupted (no-perfusion area), i.e., ischemic area (Fig. 1A). We revealed that the administration of BCL6B siRNA, which suppresses BCL6B expression, inhibits the edema in the retina of retinal vein occlusion model mice (Fig. 1B). In an experimental system using the same model, edema in the retina was markedly suppressed in mice lacking BCL6B, indicating that endogenous BCL6B acts as a regulator of retinal vascularity.
Next, BCL6B was also markedly expressed at the site of abnormal angiogenesis observed in the exudative age-related macular degeneration model mice (Fig. 2A). As a further developmental experiment, we examined using an exudative age-related macular degeneration model in crab-eating macaques. As a result, neovascularization in the model monkeys treated with BCL6B siRNA was suppressed (Fig. 2B).
Further experiments using retinal microvascular endothelial cells revealed that the Notch target gene Hes is decreased after the addition of VEGF, and that the decrease in Hes can be rescued through the suppression of BCL6B expression. We also found that the expression of phosphorylated proteins of VEGFR2, PLCg, and eNOS, which is enhanced by VEGF stimulation, is suppressed by the addition of BCL6B siRNA.
These results suggest that an increase in VEGF in the eye markedly induces BCL6B and inactivates the Notch signal, which has a vascular stabilizing effect, resulting in pericyte shedding, increased vascular permeability, and luminal formation (Fig. 3). A therapeutic approach that suppresses the expression of BCL6B, such as BCL6B siRNA, has been shown to be effective against diseases that present with vascular lesions in the eye, such as wet age-related macular degeneration and retinal vein occlusion.
Highlights of this research
- Vascular abnormalities in the eye are induced by various causes, such as aging and diabetes, resulting in vision loss and visual field defects, but the mechanisms are still unclear, and the development of therapeutic methods is eagerly awaited.
- We discovered that BCL6B functions as a molecular switch involved in vascular lesions in the eye that lead to blindness, such as choroidal angiogenesis and retinal edema.
- BCL6B is implicated in the inactivation of Notch signaling and subsequent dropout of cell adhesion molecules and pericytes in vascular endothelial cells.
- Therapeutic approaches that suppress BCL6B expression, such as nucleic acid-based drugs that target the BCL6B gene, may be effective in treating vascular lesions of the eye.
Arteriosclerosis, Thrombosis, and Vascular Biology
BCL6B Contributes to Ocular Vascular Diseases via Notch Signal Silencing
Miruto Tanaka, Shinsuke Nakamura, Tomohisa Sakaue, Takumi Yamamoto, Masashi Maekawa, Anri Nishinaka, Hiroto Yasuda, Kaori Yunoki, Yuji Sato, Masaaki Sawa, Kohichiro Yoshino, Masamitsu Shimazawa, Masahiko Hatano, Takeshi Tokuhisa, Shigeki Higashiyama, Hideaki Hara
The photo from this study made the cover of ATVB!