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

Acta Pharmacologica Sinica (2024)Cite this article

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; 20 ng/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 (5 μM) 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 (10 mg·kg−1·d−1, 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.

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Fig. 1: VEGF induces mitochondrial fission in ECs.
Fig. 2: VEGF induces DRP1 phosphorylation and mitochondrial fission via ERK signalling.
Fig. 3: Mitochondrial fission is essential for VEGF-induced angiogenesis in vitro.
Fig. 4: Enhanced mitochondrial fission is involved in VEGF-induced ROS production in ECs.
Fig. 5: Mitochondrial fission is essential for VEGF-induced upregulation of HIF-1α-dependent glycolysis in ECs.
Fig. 6: Inhibition of mitochondrial ROS decreases HIF-1α-dependent glycolysis and angiogenesis in ECs.
Fig. 7: Inhibition of DRP1 improves retinal pathological angiogenesis.

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Funding

This work was supported by grants from the National Key R&D Program of China (2022YFC3500400, 2022YFC3500405, and 2019YFE0119400), the National Natural Science Foundation of China (82270433 and 81870217), Guangdong Basic and Applied Basic Research Foundation (2023A1515011411), Rural Science and Technology Commissioner Project of Guangdong Provincial Science and Technology Department (KTPYJ2021026), and the open research funds from the Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital (202201-209).

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  1. These authors contributed equally: Shu-qi Huang, Kai-xiang Cao

Authors and Affiliations

  1. School of Basic Medical Sciences; The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Guangzhou Medical University, Guangzhou, 511436, China

    Shu-qi Huang, Kai-xiang Cao, Cai-ling Wang, Pei-ling Chen, Yi-xin Chen, Yu-ting Zhang, Shi-hui Yu, Zai-xia Bai, Shuai Guo & Yi-ming Xu

  2. Department of Rehabilitation Center, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510080, China

    Mu-xi Liao & Jun He

  3. The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Guangzhou Medical University, Guangzhou, 511520, China

    Qiao-wen Li & Guo-qi Zhang

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Contributions

YMX and SQH designed the research; SQH, KXC, QWL, YXC, CLW, PLC, YTZ, SHY, ZXB, SG and MXL performed the research; SQH, QWL, YXC, CLW, PLC, YTZ, SHY, ZXB, MXL, GQZ and JH analyzed the data; and YMX, JH, GQZ, QWL and SQH wrote the manuscript.

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Correspondence to Guo-qi Zhang, Jun He or Yi-ming Xu.

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Huang, Sq., Cao, Kx., Wang, Cl. et al. Decreasing mitochondrial fission ameliorates HIF-1α-dependent pathological retinal angiogenesis. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01262-3

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