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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. Copyright © 2017 Elsevier Inc. All rights reserved.


Toshiaki Mishima, Yoshiya Ito, Nobuyuki Nishizawa, Hideki Amano, Kazutake Tsujikawa, Kagami Miyaji, Masahiko Watanabe, Masataka Majima. RAMP1 signaling improves lymphedema and promotes lymphangiogenesis in mice. The Journal of surgical research. 2017 Nov;219:50-60

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PMID: 29078910

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