Mishima Toshiaki, Ito Yoshiya, Nishizawa Nobuyuki, Amano Hideki, Tsujikawa Kazutake, Miyaji Kagami, Watanabe Masahiko, Majima Masataka
Department of Cardiovascular Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
J Surg Res. 2017 Nov;219:50-60. doi: 10.1016/j.jss.2017.05.124. Epub 2017 Jun 23.
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.
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.
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-α 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.
RAMP1 signaling improves lymphedema and accelerates lymphangiogenesis associated with reduced recruitment of pro-inflammatory macrophages.
继发性淋巴水肿通常作为癌症手术和放射治疗的并发症出现；然而，其潜在机制尚不清楚。受体活性修饰蛋白1（RAMP1）与降钙素受体样受体形成复合物，产生降钙素基因相关肽的受体。本研究探讨RAMP1在继发性淋巴水肿期间淋巴管生成增加中是否起作用。
通过手术切除RAMP1缺陷型（RAMP1-/-）小鼠及其野生型（WT）对应小鼠尾巴皮下组织中预先存在的淋巴管，建立淋巴水肿模型。然后检查尾巴的最大直径、淋巴管生成和巨噬细胞募集情况。
与WT小鼠相比，RAMP1-/-小鼠尾巴的淋巴水肿持续存在，淋巴管生成受到抑制，病变远端边缘的血管内皮生长因子-C和血管内皮生长因子受体3表达降低。RAMP1-/-小鼠新形成的淋巴管扩张，淋巴流动受损。RAMP1由募集到伤口远端水肿尾巴组织中的巨噬细胞表达。RAMP1-/-小鼠中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）的信使核糖核酸表达在RAMP1-/-小鼠中高于WT小鼠，而编码M2巨噬细胞基因（包括白细胞介素-10）的信使核糖核酸表达较低。
RAMP1信号传导可改善淋巴水肿，并加速淋巴管生成，同时减少促炎性巨噬细胞的募集。
