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

doi:10.1631/jzus.B2500154

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

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Research Article | Updated：2025-11-04

Alamandine inhibits pathological retinal neovascularization by targeting the MrgD-mediated HIF-1α/VEGF pathway
Alamandine inhibits pathological retinal neovascularization by targeting the MrgD-mediated HIF-1α/VEGF pathway
Alamandine通过MrgD介导的HIF-1α/VEGF通路改善病理性视网膜血管新生
Journal of Zhejiang University-SCIENCE B Vol. 26, Issue 10, Pages: 1015-1036(2025)
Affiliations：

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 Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215000, China
4.Department of Cardiology, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200082, China
Funds：
DOI：10.1631/jzus.B2500154
CLC：
CSTR：
Received：27 March 2025，

Revised：2025-05-15，

Published Online：07 October 2025，

Published：20 October 2025
Accepted：

赵锟,姜亚萍,黄雯等.Alamandine通过MrgD介导的HIF-1α/VEGF通路改善病理性视网膜血管新生[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2025,26(10):1015-1036.

Kun ZHAO, Yaping JIANG, Wen HUANG, et al. Alamandine inhibits pathological retinal neovascularization by targeting the MrgD-mediated HIF-1α/VEGF pathway[J]. Journal of zhejiang university-science b, 2025, 26(10): 1015-1036.
赵锟,姜亚萍,黄雯等.Alamandine通过MrgD介导的HIF-1α/VEGF通路改善病理性视网膜血管新生[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2025,26(10):1015-1036. DOI： 10.1631/jzus.B2500154.

Kun ZHAO, Yaping JIANG, Wen HUANG, et al. Alamandine inhibits pathological retinal neovascularization by targeting the MrgD-mediated HIF-1α/VEGF pathway[J]. Journal of zhejiang university-science b, 2025, 26(10): 1015-1036. DOI： 10.1631/jzus.B2500154.

摘要

早产儿视网膜病变（ROP）是一种由缺氧导致视网膜血管病理性生长的疾病，威胁患儿的视力健康。本研究探究了肾素-血管紧张素家族中的一种新型七肽—alamandine，对低氧诱导的视网膜血管新生的影响及其潜在生物学机制。液相色谱-串联质谱法（LC-MS/MS）分析结果显示：与对照组相比，氧诱导性视网膜病变（OIR）小鼠血清和视网膜中的alamandine水平显著降低；体内alamandine的补充可显著改善低氧诱导的OIR小鼠视网膜病理性血管新生和生理性的血运重建。体外实验发现，alamandine能通过抑制HIF-1α/VEGF通路，有效抑制VEGF诱导人视网膜微血管内皮细胞（HRMECs）的增殖、迁移和成管。此外，Mas相关G蛋白偶联受体D（MrgD）拮抗剂D-Pro

，具有可逆转alamandine在体内和体外对低氧诱导的病理性血管生成的保护作用。上述研究结果表明，alamandine可通过MrgD介导的HIF-1α/VEGF通路减轻视网膜病理性新生血管的形成，为OIR的临床防治提供潜在方向。

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 hyp

oxia-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-Pro

(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.

关键词

Keywords

references

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