RAMP1 signaling improves lymphedema and promotes lymphangiogenesis in mice
RAMP1 signaling improves lymphedema and promotes lymphangiogenesis in mice
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DOI：
10.1016/j.jss.2017.05.124
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发表时间：
2017-11-01
影响因子：
2.2
通讯作者：
Majima, Masataka
中科院分区：
文献类型：
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作者：
Mishima, Toshiaki;Ito, Yoshiya;Majima, Masataka
背景：继发性淋巴水肿通常是癌症手术和放射治疗的并发症；然而，人们对其潜在机制知之甚少。受体活性修饰蛋白1 （RAMP1）与降钙素受体样受体形成复合物，生成降钙素基因相关肽受体。本研究探讨了RAMP1是否在继发性淋巴水肿中增加淋巴管生成中起作用。方法：通过手术切除RAMP1-/-缺失小鼠及其野生型（WT）小鼠尾部皮下组织中预先存在的淋巴管，产生淋巴水肿模型。然后检测尾巴的最大直径、淋巴管生成和巨噬细胞募集情况。结果：与WT小鼠相比，RAMP1-/-小鼠尾部淋巴水肿持续存在，病变远端淋巴管生成受到抑制，血管内皮生长因子- c和血管内皮生长因子受体3的表达降低。RAMP1-/-小鼠新形成的淋巴管扩张，淋巴血流受损。RAMP1是由巨噬细胞募集到伤口远端肿胀的尾部组织中表达的。RAMP1-/-小鼠的巨噬细胞数量高于WT小鼠。编码M1巨噬细胞相关基因（包括肿瘤坏死因子- α和白细胞介素-1）的信使RNA在RAMP1-/-小鼠中的表达高于WT小鼠，而编码M2巨噬细胞基因（包括白细胞介素-10）的信使RNA的表达低于WT小鼠。结论：RAMP1信号可改善淋巴水肿并加速淋巴管生成，这与促炎巨噬细胞募集减少有关。(C) 2017爱思唯尔公司版权所有。
Background: Secondary lymphedema commonly arises as a complication of cancer surgery and radiation treatment; however, the underlying mechanisms are poorly understood. Receptor activity-modifying protein 1 (RAMP1) forms a complex with calcitonin receptor-like receptor to generate the receptor for calcitonin gene-related peptide. The present study examined whether RAMP1 plays a role in increased lymphangiogenesis during secondary lymphedema.Methods: A model of lymphedema was generated by surgical removal of pre-existing lymphatic vessels from the subcutaneous tissue on the tails of RAMP1-deficient (RAMP1-/-) mice and their wild-type (WT) counterparts. The maximum diameter of the tail, lymphangiogenesis, and macrophage recruitment were then examined.Results: Compared with that in WT mice, lymphedema in the tails in RAMP1-/- mice was sustained, with suppressed lymphangiogenesis and reduced expression of vascular endothelial growth factor-C and vascular endothelial growth factor receptor 3 at the distal edge of the lesions. The newly formed lymphatic vessels in RAMP1-/- mice were dilated, with impaired lymphatic flow. RAMP1 was expressed by macrophages recruited into edematous tail tissues distal to the wound. The number of macrophages in RAMP1-/- mice was higher than that in WT mice. Expression of messenger RNA encoding M1 macrophage-related genes, including tumor necrosis factor-alpha and interleukin-1, was higher in RAMP1-/- mice than in WT mice, whereas expression of messenger RNA encoding M2 macrophage genes, including interleukin-10, was lower.Conclusions: RAMP1 signaling improves lymphedema and accelerates lymphangiogenesis associated with reduced recruitment of pro-inflammatory macrophages. (C) 2017 Elsevier Inc. All rights reserved.