Alamandine inhibits pathological retinal neovascularization by targeting the MrgD-mediated HIF-1α/VEGF pathway.

Kun ZHAO; Yaping JIANG; Wen HUANG; Yukang MAO; Yihui CHEN; Peng LI; Chuanxi YANG

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Alamandine inhibits pathological retinal neovascularization by targeting the MrgD-mediated HIF-1α/VEGF pathway.

Author: Kun ZHAO ¹ ; Yaping JIANG ² ; Wen HUANG ¹ ; Yukang MAO ¹ ; Yihui CHEN ² ; Peng LI ^{3
,

4} ; Chuanxi YANG ^{5
,

6}
Author Information

1. Department of Cardiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China.
2. Department of Ophthalmology, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200082, China.
3. Department of Cardiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China. lipeng198610@
4. com.
5. Department of Cardiology, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200082, China. lipeng198610@
6. com, 2205515@tongji.edu.cn.
Publication Type:Journal Article
Keywords: Alamandine; Mas-related G protein-coupled receptor D (MrgD); Oxygen-induced retinopathy (OIR); Pathological neovascularization; Retinopathy of prematurity (ROP); Vascular endothelial growth factor (VEGF)
MeSH: Animals; Retinal Neovascularization/prevention & control*; Mice, Inbred C57BL; Vascular Endothelial Growth Factor A/metabolism*; Humans; Mice; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism*; Oligopeptides/therapeutic use*; Signal Transduction/drug effects*; Cell Proliferation/drug effects*; Endothelial Cells/drug effects*; Retinopathy of Prematurity/drug therapy*; Apoptosis/drug effects*; Cell Movement/drug effects*; Renin-Angiotensin System/drug effects*; Cells, Cultured
From: Journal of Zhejiang University. Science. B 2025;26(10):1015-1036
CountryChina
Language:English
Abstract: Retinopathy of prematurity (ROP) is a vision-threatening disorder that leads to pathological growth of the retinal vasculature due to hypoxia. Here, we investigated the potential effects of alamandine, a novel heptapeptide in the renin-angiotensin system (RAS), on hypoxia-induced retinal neovascularization and its underlying mechanisms. In vivo, the C57BL/6J mice with oxygen-induced retinopathy (OIR) were injected intravitreally with alamandine (1.0 μmol/kg per eye). In vitro, human retinal microvascular endothelial cells (HRMECs) were utilized to investigate the effects of alamandine (10 μg/mL) on proliferation, apoptosis, migration, and tubular formation under vascular endothelial growth factor (VEGF) stimulation. Single-cell RNA sequencing (scRNA-seq) matrix data from the Gene Expression Omnibus (GEO) database and RAS-related genes from the Molecular Signatures Database (MSigDB) were sourced for subsequent analyses. By integrating scRNA-seq data across multiple species, we identified that RAS-associated endothelial cell populations were highly related to retinal neovascularization. The liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis revealed a significant decrease in alamandine levels in both the serum and retina of OIR mice compared to those in the control group. Next, alamandine ameliorated hypoxia-induced retinal pathological neovascularization and physiologic revascularization in OIR mice. In vitro, alamandine effectively mitigated VEGF-induced proliferation, scratch wound healing, and tube formation of HRMECs primarily by inhibiting the hypoxia-inducible factor-1α (HIF-1α)/VEGF pathway. Further, coincubation with D-Pro⁷ (Mas-related G protein-coupled receptor D (MrgD) antagonist) hindered the beneficial impacts of alamandine on hypoxia-induced pathological angiogenesis both in vivo and in vitro. Our findings suggested that alamandine could mitigate retinal neovascularization by targeting the MrgD-mediated HIF-1α/VEGF pathway, providing a potential therapeutic agent for OIR prevention and treatment.