adrenomedullin and Lymphatic-Diseases

Over the past decade, we have begun to appreciate that the lymphatic vascular system does more than simply return plasma back into the circulatory system and, in fact, contributes to a wide variety of normal and disease states. For this reason, much research has been devoted to understanding how lymphatic vessels form and function, with a particular interest in which molecules contribute to lymphatic vessel growth and maintenance. In the following review, we focus on a potent lymphangiogenic factor, adrenomedullin, and its known roles in lymphangiogenesis, lymphatic function, and human lymphatic disease. As one of the first, pharmacologically tractable G protein-coupled receptor pathways characterized in lymphatic endothelial cells, the continued study of adrenomedullin effects on the lymphatic system may open new avenues for the modulation of lymphatic growth and function in a variety of lymphatic-related diseases that currently have few treatments.

Topics: Adrenomedullin; Humans; Lymphangiogenesis; Lymphatic Diseases; Lymphatic System; Models, Biological; Receptors, Adrenomedullin; Signal Transduction

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.

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