Receptor Activity Modifying Protein RAMP Sub-Isoforms and Their Functional Differentiation, Which Regulates Functional Diversity of Adrenomedullin

SIMPLE SUMMARY: The body contains a variety of humoral bioactive factors and information regulation systems that maintain homeostasis. Although adrenomedullin (AM) was first identified as a vasodilator peptide, subsequent studies have revealed that it plays an essential role in homeostasis in vivo and possesses a variety of bioactivities other than vasodilation. Based on its structural homology, AM is classified as a member of the calcitonin superfamily, which includes calcitonin, calcitonin gene-related peptide (CGRP), amylin, and intermedin. Peptides belonging to the calcitonin superfamily are characterized by a partial sharing of their receptor system. One of the sub-isoforms of receptor activity-modifying protein (RAMP) binds to calcitonin receptor-like receptor (CLR), a 7-transmembrane G protein, in a one-to-one manner, and then functions as a receptor for these peptides. Among RAMP isoforms, we focused on RAMP2 and RAMP3. Each RAMP isoform is expected to be a potential therapeutic target for various diseases, including cardiovascular diseases and cancer metastasis. In this review, we outline the pathophysiological significance and functional differentiation of RAMP2 and RAMP3, as mainly revealed by the analysis of genetically engineered mice. ABSTRACT: AM knockout (AM-/-) and RAMP2 knockout (RAMP2-/-) proved lethal for mice due to impaired embryonic vascular development. Although most vascular endothelial cell-specific RAMP2 knockout (E-RAMP2-/-) mice also died during the perinatal period, a few E-RAMP2-/- mice reached adulthood. Adult E-RAMP2-/- mice developed spontaneous organ damage associated with vascular injury. In contrast, adult RAMP3 knockout (RAMP3-/-) mice showed exacerbated postoperative lymphedema with abnormal lymphatic drainage. Thus, RAMP2 is essential for vascular development and homeostasis and RAMP3 is essential for lymphatic vessel function. Cardiac myocyte-specific RAMP2 knockout mice showed early onset of heart failure as well as abnormal mitochondrial morphology and function, whereas RAMP3-/- mice exhibited abnormal cardiac lymphatics and a delayed onset of heart failure. Thus, RAMP2 is essential for maintaining cardiac mitochondrial function, while RAMP3 is essential for cardiac lymphangiogenesis. Transplantation of cancer cells into drug-inducible vascular endothelial cell-specific RAMP2 knockout mice resulted in enhanced metastasis to distant organs, whereas metastasis was suppressed in RAMP3-/- mice. RAMP2 suppresses cancer metastasis by maintaining vascular homeostasis and inhibiting vascular inflammation and pre-metastatic niche formation, while RAMP3 promotes cancer metastasis via malignant transformation of cancer-associated fibroblasts. Focusing on the diverse physiological functions of AM and the functional differentiation of RAMP2 and RAMP3 may lead to the development of novel therapeutic strategies.