Vasoprotective Activities of the Adrenomedullin-RAMP2 System in Endothelial Cells
Vasoprotective Activities of the Adrenomedullin-RAMP2 System in Endothelial Cells
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DOI：
10.1210/en.2016-1531
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发表时间：
2017-05-01
期刊：
影响因子：
4.8
通讯作者：
Shindo, Takayuki
中科院分区：
文献类型：
--
作者：
Xian, Xian;Sakurai, Takayuki;Shindo, Takayuki
新生内膜增生是冠状动脉介入治疗后动脉粥样硬化和再狭窄的主要病变。我们之前描述了肾上腺髓质素（AM）受体活性修饰蛋白（RAMP） 2系统的基本血管生成功能。在本研究中，我们利用丝性血管损伤模型评估了内源性AM-RAMP2系统的血管保护作用。我们发现RAMP2（+/）雄性小鼠的新内膜形成和血管平滑肌细胞增殖增强。RAMP2（+/）小鼠损伤血管显示出比野生型小鼠更大的巨噬细胞浸润、炎症细胞因子表达和氧化应激，再内皮化更少。在药物诱导的内皮细胞特异性RAMP2(-/-) （DI-E-RAMP2(-/-)）雄性小鼠中缺失内皮细胞特异性RAMP2后，我们观察到新内膜的形成明显大于对照组小鼠。此外，接受RAMP2（+/-）或DI-E-RAMP2（-/-）小鼠骨髓移植的小鼠血管损伤后的新内膜形成增强，表明骨髓源性细胞促进了新内膜的形成。最后，我们发现AM-RAMP2系统增强了内皮祖细胞的增殖和迁移。这些结果表明AM-RAMP2系统在血管损伤后发挥重要的血管保护作用，可能成为治疗血管疾病的治疗靶点。
Neointimal hyperplasia is the primary lesion underlying atherosclerosis and restenosis after coronary intervention. We previously described the essential angiogenic function of the adrenomedullin (AM)receptor activity-modifying protein (RAMP) 2 system. In the present study, we assessed the vasoprotective actions of the endogenous AM-RAMP2 system using a wire-induced vascular injury model. We found that neointima formation and vascular smooth muscle cell proliferation were enhanced in RAMP2(+/)male mice. The injured vessels from RAMP2(+/)mice showed greater macrophage infiltration, inflammatory cytokine expression, and oxidative stress than vessels from wild-type mice and less re-endothelialization. After endothelial cell-specific RAMP2 deletion in drug-inducible endothelial cellspecific RAMP2(-/-) (DI-E-RAMP2(-/-)) male mice, we observed markedly greater neointima formation than in control mice. In addition, neointima formation after vessel injury was enhanced in mice receiving bone marrow transplants from RAMP2(+/-) or DI-E-RAMP2(-/-) mice, indicating that bone marrow-derived cells contributed to the enhanced neointima formation. Finally, wefound that the AM-RAMP2 system augmented proliferation and migration of endothelial progenitor cells. These results demonstrate that the AM-RAMP2 system exerts crucial vasoprotective effects after vascular injury and couldbe a therapeutic target for the treatment of vascular diseases.