Vascular Endothelial Adrenomedullin-RAMP2 System Is Essential for Vascular Integrity and Organ Homeostasis
Vascular Endothelial Adrenomedullin-RAMP2 System Is Essential for Vascular Integrity and Organ Homeostasis
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DOI：
10.1161/circulationaha.112.000756
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发表时间：
2013-02-19
期刊：
影响因子：
37.8
通讯作者：
Shindo, Takayuki
中科院分区：
文献类型：
--
作者：
Koyama, Teruhide;Ochoa-Callejero, Laura;Shindo, Takayuki
背景——揭示血管系统功能完整性的机制可以提供新的治疗方法。我们之前表明，敲除广泛表达的肽肾上腺髓质素（AM）或受体活性修饰蛋白2（RAMP2）（一种AM受体辅助蛋白）会导致血管异常，并具有胚胎致死性。我们的目的是直接研究血管AM-RAMP2系统的功能。方法和结果-我们生成了内皮细胞特异性RAMP2和AM敲除小鼠（E-RAMP2（-/-）和E-AM（-/-））。大多数 E-RAMP2(-/-) 小鼠在围产期死亡。在幸存的成年人中，血管炎自发发生。随着衰老，E-RAMP2(-/-)小鼠表现出严重的器官纤维化，伴有明显的氧化应激和加速的血管衰老。后来出现肝硬化、心脏纤维化、肾积水。接下来，我们使用一系列药物诱导的 E-RAMP2(-/-) 小鼠 (DI-E-RAMP2(-/-)) 诱导成年小鼠 RAMP2 缺失，这使我们能够分析上述血管和器官损伤的最初原因。诱导后早期，出现明显水肿并伴有血管渗漏增强。体外分析表明血管渗漏是由肌动蛋白紊乱和内皮细胞脱离引起的。我们发现AM-RAMP2系统调节Rac1-GTP/RhoA-GTP比率和皮质肌动蛋白的形成，并且该系统的缺陷会导致肌动蛋白形成的破坏，导致基因删除后慢性阶段的血管和器官损伤。结论-我们的研究结果表明，AM-RAMP2系统是从产前阶段到成年期血管完整性和稳态的关键决定因素。此外，我们的模型展示了内皮细胞如何调节血管完整性以及它们的失调如何导致器官损伤。 （流通。2013 年；127：842-853。）
Background-Revealing the mechanisms underlying the functional integrity of the vascular system could make available novel therapeutic approaches. We previously showed that knocking out the widely expressed peptide adrenomedullin (AM) or receptor activity-modifying protein 2 (RAMP2), an AM-receptor accessory protein, causes vascular abnormalities and is embryonically lethal. Our aim was to investigate the function of the vascular AM-RAMP2 system directly.Methods and Results-We generated endothelial cell-specific RAMP2 and AM knockout mice (E-RAMP2(-/-) and E-AM(-/-)). Most E-RAMP2(-/-) mice died perinatally. In surviving adults, vasculitis occurred spontaneously. With aging, E-RAMP2(-/-) mice showed severe organ fibrosis with marked oxidative stress and accelerated vascular senescence. Later, liver cirrhosis, cardiac fibrosis, and hydronephrosis developed. We next used a line of drug-inducible E-RAMP2(-/-) mice (DI-E-RAMP2(-/-)) to induce RAMP2 deletion in adults, which enabled us to analyze the initial causes of the aforementioned vascular and organ damage. Early after the induction, pronounced edema with enhanced vascular leakage occurred. In vitro analysis revealed the vascular leakage to be caused by actin disarrangement and detachment of endothelial cells. We found that the AM-RAMP2 system regulates the Rac1-GTP/RhoA-GTP ratio and cortical actin formation and that a defect in this system causes the disruption of actin formation, leading to vascular and organ damage at the chronic stage after the gene deletion.Conclusions-Our findings show that the AM-RAMP2 system is a key determinant of vascular integrity and homeostasis from prenatal stages through adulthood. Furthermore, our models demonstrate how endothelial cells regulate vascular integrity and how their dysregulation leads to organ damage. (Circulation. 2013;127:842-853.)