RAMP1 signaling improves lymphedema and promotes lymphangiogenesis in mice

J Surg Res. 2017 Nov:219:50-60. doi: 10.1016/j.jss.2017.05.124. Epub 2017 Jun 23.


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-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.

Conclusions: RAMP1 signaling improves lymphedema and accelerates lymphangiogenesis associated with reduced recruitment of pro-inflammatory macrophages.

Keywords: Lymphangiogenesis; Lymphedema; Macrophage; RAMP1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Lymphangiogenesis / physiology*
  • Lymphedema / etiology
  • Lymphedema / metabolism*
  • Lymphedema / physiopathology
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Postoperative Complications / metabolism*
  • Postoperative Complications / physiopathology
  • Receptor Activity-Modifying Protein 1 / deficiency
  • Receptor Activity-Modifying Protein 1 / metabolism*
  • Signal Transduction


  • Biomarkers
  • Ramp1 protein, mouse
  • Receptor Activity-Modifying Protein 1