Targeting circular RNA-MET for anti-angiogenesis treatment via inhibiting endothelial tip cell specialization

Mu-Di Yao; Qin Jiang; Yan Ma; Yan Zhu; Qiu-Yang Zhang; Ze-Hui Shi; Chen Zhao; Biao Yan

doi:10.1016/j.ymthe.2022.01.012

Targeting circular RNA-MET for anti-angiogenesis treatment via inhibiting endothelial tip cell specialization

Mol Ther. 2022 Mar 2;30(3):1252-1264. doi: 10.1016/j.ymthe.2022.01.012. Epub 2022 Jan 7.

Authors

Mu-Di Yao¹, Qin Jiang², Yan Ma³, Yan Zhu³, Qiu-Yang Zhang², Ze-Hui Shi⁴, Chen Zhao⁵, Biao Yan⁶

Affiliations

¹ Eye Institute, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China; NHC Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China; Shanghai Key Laboratory of Visual Impairment and Restoration (Fudan University), Shanghai, China.
² The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China; The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China.
³ The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China.
⁴ Eye Institute, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China; NHC Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China.
⁵ Eye Institute, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
⁶ Eye Institute, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China; NHC Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China; Shanghai Key Laboratory of Visual Impairment and Restoration (Fudan University), Shanghai, China. Electronic address: biao.yan@fdeent.org.

Abstract

Endothelial tip cell specialization plays an essential role in angiogenesis, which is tightly regulated by the complicated gene regulatory network. Circular RNA (circRNA) is a type of covalently closed non-coding RNA that regulates gene expression in eukaryotes. Here, we report that the levels of circMET expression are significantly upregulated in the retinas of mice with oxygen-induced retinopathy, choroidal neovascularization, and diabetic retinopathy. circMET silencing significantly reduces pathological angiogenesis and inhibits tip cell specialization in vivo. circMET silencing also decreases endothelial migration and sprouting in vitro. Mechanistically, circMET regulates endothelial sprouting and pathological angiogenesis by acting as a scaffold to enhance the interaction between IGF2BP2 and NRARP/ESM1. Clinically, circMET is significantly upregulated in the clinical samples of the patients of diabetic retinopathy. circMET silencing could reduce diabetic vitreous-induced endothelial sprouting and retinal angiogenesis in vivo. Collectively, these data identify a circRNA-mediated mechanism that coordinates tip cell specialization and pathological angiogenesis. circMET silencing is an exploitable therapeutic approach for the treatment of neovascular diseases.

Keywords: circular RNA; endothelial sprouting; mRNA stability; pathological angiogenesis; tip cell.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Choroidal Neovascularization* / genetics
Diabetic Retinopathy* / drug therapy
Diabetic Retinopathy* / genetics
Endothelial Cells / metabolism
Humans
Mice
Mice, Inbred C57BL
RNA, Circular / genetics
RNA-Binding Proteins / metabolism
Retina / metabolism

Substances

IGF2BP2 protein, human
RNA, Circular
RNA-Binding Proteins