Adrenomedullin signaling is necessary for murine lymphatic vascular development

J Clin Invest. 2008 Jan;118(1):40-50. doi: 10.1172/JCI33302.


The lymphatic vascular system mediates fluid homeostasis, immune defense, and tumor metastasis. Only a handful of genes are known to affect the development of the lymphatic vasculature, and even fewer represent therapeutic targets for lymphatic diseases. Adrenomedullin (AM) is a multifunctional peptide vasodilator that transduces its effects through the calcitonin receptor-like receptor (calcrl) when the receptor is associated with a receptor activity-modifying protein (RAMP2). Here we report on the involvement of these genes in lymphangiogenesis. AM-, calcrl-, or RAMP2-null mice died mid-gestation after development of interstitial lymphedema. This conserved phenotype provided in vivo evidence that these components were required for AM signaling during embryogenesis. A conditional knockout line with loss of calcrl in endothelial cells confirmed an essential role for AM signaling in vascular development. Loss of AM signaling resulted in abnormal jugular lymphatic vessels due to reduction in lymphatic endothelial cell proliferation. Furthermore, AM caused enhanced activation of ERK signaling in human lymphatic versus blood endothelial cells, likely due to induction of CALCRL gene expression by the lymphatic transcriptional regulator Prox1. Collectively, our studies identify a class of genes involved in lymphangiogenesis that represent a pharmacologically tractable system for the treatment of lymphedema or inhibition of tumor metastasis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenomedullin / genetics
  • Adrenomedullin / metabolism*
  • Animals
  • Calcitonin Receptor-Like Protein
  • Cell Proliferation
  • Embryo Loss / genetics
  • Embryo Loss / pathology
  • Embryonic Development / physiology*
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Female
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Homeostasis / physiology*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lymphatic Diseases / genetics
  • Lymphatic Diseases / metabolism
  • Lymphatic Diseases / pathology
  • Lymphatic Vessels / embryology*
  • Lymphatic Vessels / pathology
  • Lymphedema / genetics
  • Lymphedema / metabolism
  • Lymphedema / pathology
  • MAP Kinase Signaling System / physiology*
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Neoplasm Metastasis
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Neovascularization, Physiologic / physiology*
  • Pregnancy
  • Receptor Activity-Modifying Protein 2
  • Receptor Activity-Modifying Proteins
  • Receptors, Calcitonin
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism


  • CALCRL protein, human
  • Calcitonin Receptor-Like Protein
  • Calcrl protein, mouse
  • Homeodomain Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • RAMP2 protein, human
  • Ramp2 protein, mouse
  • Receptor Activity-Modifying Protein 2
  • Receptor Activity-Modifying Proteins
  • Receptors, Calcitonin
  • Tumor Suppressor Proteins
  • prospero-related homeobox 1 protein
  • Adrenomedullin