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

Shu-qi Huang1,2, Kai-xiang Cao1,2, Cai-ling Wang1,2, Pei-ling Chen1,2, Yi-xin Chen1,2, Yu-ting Zhang1,2, Shi-hui Yu1,2, Zai-xia Bai1,2, Shuai Guo1,2, Mu-xi Liao3, Qiao-wen Li4, Guo-qi Zhang4, Jun He3, Yi-ming Xu1,2
1 School of Basic Medical Sciences
2 The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Guangzhou Medical University, Guangzhou 511436, China
3 Department of Rehabilitation Center, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510080, China
4 The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Guangzhou Medical University, Guangzhou 511520, China
Correspondence to: Guo-qi Zhang:, Jun He:, Yi-ming Xu:,
DOI: 10.1038/s41401-024-01262-3
Received: 27 August 2023
Accepted: 4 March 2024
Advance online: 2 April 2024


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.

Keywords: pathological angiogenesis; mitochondrial fission; Dynamin-related protein 1; Mdivi-1; glycolysis; ROS

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