Adrenomedullin-Receptor Activity-Modifying Protein 2 System Ameliorates Subretinal Fibrosis by Suppressing Epithelial-Mesenchymal Transition in Age-Related Macular Degeneration
Adrenomedullin-Receptor Activity-Modifying Protein 2 System Ameliorates Subretinal Fibrosis by Suppressing Epithelial-Mesenchymal Transition in Age-Related Macular Degeneration
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DOI：
10.1016/j.ajpath.2020.12.012
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发表时间：
2021-03-19
影响因子：
6
通讯作者：
Shindo，Takayuki
中科院分区：
文献类型：
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作者：
Tanaka，Masaaki;Kakihara，Shinji;Shindo，Takayuki
视网膜相关性黄斑变性（AMD）是视力损害的主要原因。用于治疗AMD的抗血管内皮生长因子药物具有诱导视网膜下纤维化的风险。我们研究了肾上腺髓质素（AM），一种血管活性肽，及其受体活性修饰蛋白2，RAMP 2，调节血管稳态和抑制纤维化。在激光诱导的脉络膜新生血管形成（LI-CNV）（AMD的小鼠模型）后评估AM-RAMP 2系统的治疗潜力。与野生型小鼠相比，AM和RAMP 2基因敲除小鼠的新生血管形成、视网膜下纤维化和巨噬细胞侵袭均增强。玻璃体内注射AM可抑制上述病理变化。对LI-CNV加或不加AM后脉络膜的综合基因表达分析显示，AM下调了纤维化相关分子，包括Tgfb、Cxcr 4、Ccn 2和Thbs 1。在视网膜色素上皮细胞中，共同给予转化生长因子-β和肿瘤坏死因子-α诱导上皮-间质转化，这也被AM阻止。最后，转化生长因子-β和C-X-C趋化因子受体4型（CXCR 4）抑制剂消除了RAMP 2敲除小鼠和野生型小鼠之间视网膜下纤维化的差异。这些发现表明AM-RAMP 2系统通过抑制上皮-间充质转化来抑制LI-CNV中的视网膜下纤维化。
Age-related macular degeneration (AMD) is a leading cause of visual impairment. Anti–vascular endothelial growth factor drugs used to treat AMD carry the risk of inducing subretinal fibrosis. We investigated the use of adrenomedullin (AM), a vasoactive peptide, and its receptor activity-modifying protein 2, RAMP2, which regulate vascular homeostasis and suppress fibrosis. The therapeutic potential of the AM-RAMP2 system was evaluated after laser-induced choroidal neovascularization (LI-CNV), a mouse model of AMD. Neovascular formation, subretinal fibrosis, and macrophage invasion were all enhanced in both AM and RAMP2 knockout mice compared with those in wild-type mice. These pathologic changes were suppressed by intravitreal injection of AM. Comprehensive gene expression analysis of the choroid after LI-CNV with or without AM administration revealed that fibrosis-related molecules, includingTgfb,Cxcr4,Ccn2, andThbs1, were all down-regulated by AM. In retinal pigment epithelial cells, co-administration of transforming growth factor-β and tumor necrosis factor-α induced epithelial-mesenchymal transition, which was also prevented by AM. Finally, transforming growth factor-β and C-X-C chemokine receptor type 4 (CXCR4) inhibitors eliminated the difference in subretinal fibrosis between RAMP2 knockout and wild-type mice. These findings suggest the AM-RAMP2 system suppresses subretinal fibrosis in LI-CNV by suppressing epithelial-mesenchymal transition.