Mitochondrial control of hypoxia-induced pathological retinal angiogenesis

IF 9.2 1区医学 Q1 PERIPHERAL VASCULAR DISEASE

Angiogenesis Pub Date : 2024-08-03 DOI:10.1007/s10456-024-09940-w

Hitomi Yagi, Myriam Boeck, Shen Nian, Katherine Neilsen, Chaomei Wang, Jeff Lee, Yan Zeng, Matthew Grumbine, Ian R. Sweet, Taku Kasai, Kazuno Negishi, Sasha A. Singh, Masanori Aikawa, Ann Hellström, Lois E. H. Smith, Zhongjie Fu

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引用次数: 0

Abstract

Objective

Pathological retinal neovascularization is vision-threatening. In mouse oxygen-induced retinopathy (OIR) we sought to define mitochondrial respiration changes longitudinally during hyperoxia-induced vessel loss and hypoxia-induced neovascularization, and to test interventions addressing those changes to prevent neovascularization.

Methods

OIR was induced in C57BL/6J mice and retinal vasculature was examined at maximum neovessel formation. We assessed total proteome changes and the ratio of mitochondrial to nuclear DNA copy numbers (mtDNA/nDNA) of OIR vs. control retinas, and mitochondrial oxygen consumption rates (OCR) in ex vivo OIR vs. control retinas (BaroFuse). Pyruvate vs. vehicle control was supplemented to OIR mice either prior to or during neovessel formation.

Results

In OIR vs. control retinas, global proteomics showed decreased retinal mitochondrial respiration at peak neovascularization. OCR and mtDNA/nDNA were also decreased at peak neovascularization suggesting impaired mitochondrial respiration. In vivo pyruvate administration during but not prior to neovessel formation (in line with mitochondrial activity time course) suppressed NV.

Conclusions

Mitochondrial energetics were suppressed during retinal NV in OIR. Appropriately timed supplementation of pyruvate may be a novel approach in neovascular retinal diseases.

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线粒体控制缺氧诱导的病理性视网膜血管生成

目的病理性视网膜新生血管会威胁视力。在小鼠氧诱导视网膜病变（OIR）中，我们试图确定高氧诱导血管缺失和低氧诱导新生血管形成过程中线粒体呼吸的纵向变化，并测试针对这些变化的干预措施，以防止新生血管形成。我们评估了OIR与对照组视网膜的总蛋白质组变化、线粒体与核DNA拷贝数之比（mtDNA/nDNA），以及OIR与对照组视网膜（BaroFuse）的线粒体耗氧率（OCR）。结果在 OIR 与对照组视网膜中，全蛋白质组学显示在新生血管形成高峰期视网膜线粒体呼吸减少。在新生血管形成高峰期，OCR 和 mtDNA/nDNA 也出现下降，表明线粒体呼吸功能受损。在新血管形成期间而非之前（与线粒体活动时间进程一致）体内注射丙酮酸可抑制新血管形成。适时补充丙酮酸可能是治疗新生血管性视网膜疾病的一种新方法。

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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.