Botulinum neurotoxin serotype A inhibited ocular angiogenesis through modulating glial activation via SOCS3.

IF 9.2 1区医学 Q1 PERIPHERAL VASCULAR DISEASE Angiogenesis Pub Date : 2024-06-26 DOI:10.1007/s10456-024-09935-7

Austin T Gregg, Tianxi Wang, Manon Szczepan, Enton Lam, Hitomi Yagi, Katherine Neilsen, Xingyan Wang, Lois E H Smith, Ye Sun

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Abstract

Background: Pathological angiogenesis causes significant vision loss in neovascular age-related macular degeneration and other retinopathies with neovascularization (NV). Neuronal/glial-vascular interactions influence the release of angiogenic and neurotrophic factors. We hypothesized that botulinum neurotoxin serotype A (BoNT/A) modulates pathological endothelial cell proliferation through glial cell activation and growth factor release.

Methods: A laser-induced choroidal NV (CNV) was employed to investigate the anti-angiogenic effects of BoNT/A. Fundus fluorescence angiography, immunohistochemistry, and real-time PCR were used to assess BoNT/A efficacy in inhibiting CNV and the molecular mechanisms underlying this inhibition. Neuronal and glial suppressor of cytokine signaling 3 (SOCS3) deficient mice were used to investigate the molecular mechanisms of BoNT/A in inhibiting CNV via SOCS3.

Findings: In laser-induced CNV mice with intravitreal BoNT/A treatment, CNV lesions decreased > 30%; vascular leakage and retinal glial activation were suppressed; and Socs3 mRNA expression was induced while vascular endothelial growth factor A (Vegfa) mRNA expression was suppressed. The protective effects of BoNT/A on CNV development were diminished in mice lacking neuronal/glial SOCS3.

Conclusion: BoNT/A suppressed laser-induced CNV and glial cell activation, in part through SOCS3 induction in neuronal/glial cells. BoNT/A treatment led to a decrease of pro-angiogenic factors, including VEGFA, highlighting the potential of BoNT/A as a therapeutic intervention for pathological angiogenesis in retinopathies.

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肉毒杆菌神经毒素血清型A通过SOCS3调节神经胶质活化抑制眼部血管生成

背景：病理性血管生成会导致新生血管性老年黄斑变性和其他伴有新生血管（NV）的视网膜病变的视力严重下降。神经元/胶质细胞-血管之间的相互作用会影响血管生成因子和神经营养因子的释放。我们假设肉毒杆菌神经毒素血清型 A（BoNT/A）通过激活神经胶质细胞和释放生长因子来调节病理性内皮细胞增殖：方法：采用激光诱导的脉络膜无视网膜病变（CNV）来研究 BoNT/A 的抗血管生成作用。眼底荧光血管造影术、免疫组化和实时 PCR 被用来评估 BoNT/A 在抑制 CNV 方面的功效以及这种抑制作用的分子机制。利用神经元和胶质细胞因子信号转导抑制因子 3（SOCS3）缺陷小鼠研究 BoNT/A 通过 SOCS3 抑制 CNV 的分子机制：研究结果：激光诱导的CNV小鼠经玻璃体内BoNT/A治疗后，CNV病变减少> 30%；血管渗漏和视网膜胶质细胞活化被抑制；Socs3 mRNA表达被诱导，而血管内皮生长因子A（Vegfa）mRNA表达被抑制。在缺乏神经元/胶质细胞 SOCS3 的小鼠中，BoNT/A 对 CNV 发生的保护作用减弱：结论：BoNT/A抑制了激光诱导的CNV和神经胶质细胞活化，部分原因是通过诱导神经元/神经胶质细胞中的SOCS3。BoNT/A治疗导致促血管生成因子（包括VEGFA）减少，突出了BoNT/A作为视网膜病变中病理性血管生成治疗干预的潜力。

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来源期刊

Angiogenesis PERIPHERAL VASCULAR DISEASE-

CiteScore

21.90

自引率

8.20%

发文量

审稿时长

6-12 weeks

期刊介绍： Angiogenesis, a renowned international journal, seeks to publish high-quality original articles and reviews on the cellular and molecular mechanisms governing angiogenesis in both normal and pathological conditions. By serving as a primary platform for swift communication within the field of angiogenesis research, this multidisciplinary journal showcases pioneering experimental studies utilizing molecular techniques, in vitro methods, animal models, and clinical investigations into angiogenic diseases. Furthermore, Angiogenesis sheds light on cutting-edge therapeutic strategies for promoting or inhibiting angiogenesis, while also highlighting fresh markers and techniques for disease diagnosis and prognosis.