广州医科大学Yi-ming Xu、Guo-qi Zhang和广州中医药大学第一附属医院Jun He研究团队，发现减少线粒体分裂可改善HIF-1α依赖的病理性视网膜血管生成。2024年4月2日出版的《中国药理学报》杂志发表了这项成果。

在本研究中，研究人员揭示了线粒体动力学在病理性视网膜血管生成中的作用。研究发现，血管内皮生长因子（VEGF；20 ng/ml）通过促进动态相关蛋白1（DRP1）的磷酸化诱导HUVECs线粒体裂变。敲除DRP1或利用DRP1抑制剂Mdivi-1（5 μM）进行预处理可阻止VEGF诱导的HUVECs细胞迁移、增殖和血管形成。

研究证实，VEGF处理会增加HUVECs中线粒体活性氧（ROS）的产生，而线粒体ROS是HIF-1α依赖性糖酵解以及增殖、迁移和血管形成所必需的，线粒体裂变抑制剂可阻止VEGF诱导的线粒体ROS产生。在氧诱导视网膜病变（OIR）小鼠模型中，研究人员发现DRP1在新生血管丛内皮细胞中高表达。从出生后第13至第15天，连续三天给予Mdivi-1（10 mg-kg-1-d-1，i.p.）可显著缓解视网膜中病理性血管的生成。

该研究结果表明，靶向线粒体裂变可能是增殖性视网膜病变，和其他依赖病理性血管生成疾病的一种治疗策略。

研究人员表示，在许多疾病发生过程中血管生成起着至关重要的作用，例如早产儿视网膜病变等眼疾造成的不可逆失明。内皮线粒体是不断发生融合和裂变的动态细胞器，其是通过协调活性氧产生、钙信号以及新陈代谢来调控血管生成的关键信号枢纽。

附：英文原文

Title: Decreasing mitochondrial fission ameliorates HIF-1α-dependent pathological retinal angiogenesis

Author: Huang, Shu-qi, Cao, Kai-xiang, Wang, Cai-ling, Chen, Pei-ling, Chen, Yi-xin, Zhang, Yu-ting, Yu, Shi-hui, Bai, Zai-xia, Guo, Shuai, Liao, Mu-xi, Li, Qiao-wen, Zhang, Guo-qi, He, Jun, Xu, Yi-ming

Issue&Volume: 2024-04-02

Abstract: Angiogenesis plays a critical role in many pathological processes, including irreversible blindness in eye diseases such as retinopathy of prematurity. Endothelial mitochondria are dynamic organelles that undergo constant fusion and fission and are critical signalling hubs that modulate angiogenesis by coordinating reactive oxygen species (ROS) production and calcium signalling and metabolism. In this study, we investigated the role of mitochondrial dynamics in pathological retinal angiogenesis. We showed that treatment with vascular endothelial growth factor (VEGF; 20ng/ml) induced mitochondrial fission in HUVECs by promoting the phosphorylation of dynamin-related protein 1 (DRP1). DRP1 knockdown or pretreatment with the DRP1 inhibitor Mdivi-1 (5μM) blocked VEGF-induced cell migration, proliferation, and tube formation in HUVECs. We demonstrated that VEGF treatment increased mitochondrial ROS production in HUVECs, which was necessary for HIF-1α-dependent glycolysis, as well as proliferation, migration, and tube formation, and the inhibition of mitochondrial fission prevented VEGF-induced mitochondrial ROS production. In an oxygen-induced retinopathy (OIR) mouse model, we found that active DRP1 was highly expressed in endothelial cells in neovascular tufts. The administration of Mdivi-1 (10mg·kg1·d1, i.p.) for three days from postnatal day (P) 13 until P15 significantly alleviated pathological angiogenesis in the retina. Our results suggest that targeting mitochondrial fission may be a therapeutic strategy for proliferative retinopathies and other diseases that are dependent on pathological angiogenesis.

DOI: 10.1038/s41401-024-01262-3

Source: https://www.nature.com/articles/s41401-024-01262-3