Adrenomedullin-RAMP2 System Is Crucially Involved in Retinal Angiogenesis
Adrenomedullin-RAMP2 System Is Crucially Involved in Retinal Angiogenesis
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DOI：
10.1016/j.ajpath.2013.02.015
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发表时间：
2013-06-01
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：
Iesato, Yasuhiro;Toriyama, Yuichi;Shindo, Takayuki
肾上腺髓质素（ADM）是一种内源性多肽，首先被鉴定为强血管舒张分子。我们先前表明，在小鼠中，ADM（ADM（-/-））或其受体调节蛋白RAMP 2（RAMP 2（-/-））的纯合敲除由于异常血管发育而具有胚胎致死性，从而证明了ADM及其受体信号传导对血管发育的重要性。ADM在视网膜中的表达强烈诱导缺血，然而，其在视网膜病理生理学中的作用仍然未知。在这里，我们使用杂合ADM和RAMP 2敲除小鼠模型（分别为ADM（+/-）或RAMP 2（+/-））分析了氧诱导的视网膜病变（OIR）。此外，我们使用可诱导的内皮细胞特异性RAMP 2敲除小鼠系（DI-E-RAMP 2（-/-））分析了ADM-RAMP 2系统在视网膜血管生成早期阶段的作用。最后，我们评估了抗体诱导的ADM阻断在OIR中控制病理性视网膜血管生成的能力。在OIR中，ADM（+/-）视网膜中的新生血管簇、无血管区和缺氧区均小于野生型小鼠。ADM+/-视网膜也表现出VEGF和eNOS表达水平降低。DI-E-RAMP 2-/-在发育的早期阶段显示异常的视网膜血管模式。但ADM可促进视网膜内皮细胞的增殖和迁移。最后，我们发现玻璃体内注射抗ADM抗体减少了病理性视网膜血管生成。总之，ADM-RAMP 2系统是至关重要的参与视网膜血管生成。ADM及其受体系统是控制病理性视网膜血管生成的潜在治疗靶点。
Adrenomedullin (ADM) is an endogenous peptide first identified as a strong vasodilating molecule. We previously showed that in mice, homozygous knockout of ADM (ADM(-/-)) or its receptor regulating protein, RAMP2 (RAMP2(-/-)), is embryonically lethal due to abnormal vascular development, thereby demonstrating the importance of ADM and its receptor signaling to vascular development. ADM expression in the retina is strongly induced by ischemia; however, its role in retinal pathophysiology remains unknown. Here, we analyzed oxygen-induced retinopathy (OIR) using heterozygous ADM and RAMP2 knockout mice models (ADM(+/-) or RAMP2(+/-) respectively). In addition, we analyzed the role of the ADM-RAMP2 system during earlier stages of retinal angiogenesis using an inducible endothelial cell-specific RAMP2 knockout mouse Line (DI-E-RAMP2(-/-)). Finally, we assessed the ability of antibody-induced ADM blockade to control pathological retinal angiogenesis in OIR. In OIR, neovascular tufts, avascular zones, and hypoxic areas were all smaller in ADM(+/-) retinas compared with wild-type mice. ADM+/- retinas also exhibited reduced levels of VEGF and eNOS expression. DI-E-RAMP2-/- showed abnormal retinal vascular patterns in the early stages of development. However, ADM enhanced the proliferation and migration of retinal endothelial cells. Finally, we found intravitreal injection of anti-ADM antibody reduced pathological retinal angiogenesis. In conclusion, the ADM-RAMP2 system is crucially involved in retinal angiogenesis. ADM and its receptor system are potential therapeutic targets for controlling pathological retinal angiogenesis.