{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T02:52:02Z","timestamp":1780455122159,"version":"3.54.1"},"reference-count":33,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,5,21]],"date-time":"2022-05-21T00:00:00Z","timestamp":1653091200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/biology11050788","type":"journal-article","created":{"date-parts":[[2022,5,21]],"date-time":"2022-05-21T09:18:08Z","timestamp":1653124688000},"page":"788","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Receptor Activity Modifying Protein RAMP Sub-Isoforms and Their Functional Differentiation, Which Regulates Functional Diversity of Adrenomedullin"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1262-0819","authenticated-orcid":false,"given":"Takayuki","family":"Shindo","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto 390-8621, Japan"},{"name":"Department of Life Innovation, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto 390-8621, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megumu","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto 390-8621, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiko","family":"Kamiyoshi","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto 390-8621, Japan"},{"name":"Department of Life Innovation, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto 390-8621, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuka","family":"Ichikawa-Shindo","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto 390-8621, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisaka","family":"Kawate","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto 390-8621, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayuki","family":"Sakurai","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto 390-8621, Japan"},{"name":"Department of Life Innovation, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto 390-8621, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1006\/bbrc.1993.1451","article-title":"Adrenomedullin: A Novel Hypotensive Peptide Isolated from Human Pheochromocytoma","volume":"192","author":"Kitamura","year":"1993","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.peptides.2018.04.004","article-title":"Regulation of Cardiovascular Development and Homeostasis by the Adrenomedullin-RAMP System","volume":"111","author":"Shindo","year":"2019","journal-title":"Peptides"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"246","DOI":"10.2174\/13892037113149990044","article-title":"Adrenomedullin as a Potential Therapeutic Agent for Inflammatory Bowel Disease","volume":"14","author":"Ashizuka","year":"2013","journal-title":"Curr. Protein Pept. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1007\/s10620-015-3917-0","article-title":"Adrenomedullin Therapy in Patients with Refractory Ulcerative Colitis: A Case Series","volume":"61","author":"Ashizuka","year":"2016","journal-title":"Dig. Dis. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/30666","article-title":"RAMPs Regulate the Transport and Ligand Specificity of the Calcitonin-Receptor-Like Receptor","volume":"393","author":"McLatchie","year":"1998","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1964","DOI":"10.1161\/hc4101.097111","article-title":"Vascular Abnormalities and Elevated Blood Pressure in Mice Lacking Adrenomedullin Gene","volume":"104","author":"Shindo","year":"2001","journal-title":"Circulation"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1172\/JCI33022","article-title":"The GPCR Modulator Protein RAMP2 Is Essential for Angiogenesis and Vascular Integrity","volume":"118","author":"Sakurai","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1161\/CIRCULATIONAHA.112.000756","article-title":"Vascular Endothelial Adrenomedullin-RAMP2 System Is Essential for Vascular Integrity and Organ Homeostasis","volume":"127","author":"Koyama","year":"2013","journal-title":"Circulation"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.mvr.2008.09.012","article-title":"The Actin Cytoskeleton in Endothelial Cell Phenotypes","volume":"77","author":"Prasain","year":"2009","journal-title":"Microvasc. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1210\/en.2016-1531","article-title":"Vasoprotective Activities of the Adrenomedullin-RAMP2 System in Endothelial Cells","volume":"158","author":"Xian","year":"2017","journal-title":"Endocrinology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.yjmcc.2014.09.017","article-title":"Functional Differentiation of RAMP2 and RAMP3 in Their Regulation of the Vascular System","volume":"77","author":"Yamauchi","year":"2014","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1161\/HYPERTENSIONAHA.111.00647","article-title":"Novel Regulation of Cardiac Metabolism and Homeostasis by the Adrenomedullin-Receptor Activity-Modifying Protein 2 System","volume":"61","author":"Yoshizawa","year":"2013","journal-title":"Hypertension"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"bqab001","DOI":"10.1210\/endocr\/bqab001","article-title":"Adrenomedullin-RAMP2 and -RAMP3 Systems Regulate Cardiac Homeostasis During Cardiovascular Stress","volume":"162","author":"Cui","year":"2021","journal-title":"Endocrinology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/35093131","article-title":"CREB Regulates Hepatic Gluconeogenesis Through the coactivator PGC-1","volume":"413","author":"Herzig","year":"2001","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1161\/ATVBAHA.114.304752","article-title":"Gap Junction Coupling Is Required for Tumor Cell Migration Through Lymphatic Endothelium","volume":"35","author":"Karpinich","year":"2015","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1161\/CIRCRESAHA.118.313835","article-title":"Adrenomedullin Induces Cardiac Lymphangiogenesis After Myocardial Infarction and Regulates Cardiac Edema via Connexin 43","volume":"124","author":"Trincot","year":"2019","journal-title":"Circ. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.peptides.2018.03.012","article-title":"Adrenomedullin: Continuing to Explore Cardioprotection","volume":"111","author":"Tsuruda","year":"2019","journal-title":"Peptides"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"23345","DOI":"10.1074\/jbc.271.38.23345","article-title":"Adrenomedullin Expression in Human Tumor Cell Lines. Its Potential Role as an Autocrine Growth Factor","volume":"271","author":"Miller","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1186\/s13058-014-0458-y","article-title":"Tumor-Expressed Adrenomedullin Accelerates Breast Cancer Bone Metastasis","volume":"16","author":"Siclari","year":"2014","journal-title":"Breast Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2666","DOI":"10.1158\/0008-5472.CAN-06-3362","article-title":"Adrenomedullin Is Expressed in Pancreatic Cancer and Stimulates Cell Proliferation and Invasion in an Autocrine Manner via the Adrenomedullin Receptor, ADMR","volume":"67","author":"Ramachandran","year":"2007","journal-title":"Cancer Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1093\/cvr\/cvw166","article-title":"The Endothelial Adrenomedullin-RAMP2 System Regulates Vascular Integrity and Suppresses Tumour Metastasis","volume":"111","author":"Tanaka","year":"2016","journal-title":"Cardiovasc. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1002\/iub.1059","article-title":"The Role of Endothelial-Mesenchymal Transition in Development and Pathological Process","volume":"64","author":"Lin","year":"2012","journal-title":"IUBMB Life"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1038\/ncb1507","article-title":"Tumour-Mediated Upregulation of Chemoattractants and Recruitment of Myeloid Cells Predetermines Lung Metastasis","volume":"8","author":"Hiratsuka","year":"2006","journal-title":"Nat. Cell Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1038\/ncb1794","article-title":"The S100A8-Serum Amyloid A3-TLR4 Paracrine Cascade Establishes a Pre-Metastatic Phase","volume":"10","author":"Hiratsuka","year":"2008","journal-title":"Nat. Cell Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.1038\/ncomms2856","article-title":"Primary Tumours Modulate Innate Immune Signalling to Create Pre-Metastatic Vascular Hyperpermeability Foci","volume":"4","author":"Hiratsuka","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1914","DOI":"10.1038\/s41388-019-1112-z","article-title":"Deficiency of the Adrenomedullin-RAMP3 System Suppresses Metastasis Through the Modification of Cancer-Associated Fibroblasts","volume":"39","author":"Dai","year":"2020","journal-title":"Oncogene"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1186\/1476-4598-12-168","article-title":"Podoplanin Expression in Cancer-associated Fibroblasts Enhances Tumor Progression of Invasive Ductal Carcinoma of the Pancreas","volume":"12","author":"Shindo","year":"2013","journal-title":"Mol. Cancer."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"241","DOI":"10.2334\/josnusd.54.241","article-title":"Podoplanin Promotes Cell Migration via the EGF-Src-Cas Pathway in Oral Squamous Cell Carcinoma Cell Lines","volume":"54","author":"Inoue","year":"2012","journal-title":"J. Oral Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1177\/0333102417736900","article-title":"Recognizing the Role of CGRP and CGRP Receptors in Migraine and Its Treatment","volume":"39","author":"Edvinsson","year":"2019","journal-title":"Cephalalgia"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"17488","DOI":"10.1038\/s41598-017-17573-x","article-title":"Small Molecules Related to Adrenomedullin Reduce Tumor Burden in a Mouse Model of Colitis-associated Colon Cancer","volume":"7","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s40635-019-0255-0","article-title":"Adrecizumab, a Non-neutralizing Anti-adrenomedullin Antibody, Improves Haemodynamics and Attenuates Myocardial Oxidative Stress in Septic Rats","volume":"7","author":"Blet","year":"2019","journal-title":"Intensive Care Med. Exp."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.1110\/ps.036012.108","article-title":"Crystal Structure of the Human Receptor Activity-Modifying Protein 1 Extracellular Domain","volume":"17","author":"Kusano","year":"2008","journal-title":"Protein Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1002\/pro.2003","article-title":"Structural Basis for Extracellular Interactions Between Calcitonin Receptor-Like Receptor and Receptor Activity-Modifying Protein 2 for Adrenomedullin-Specific Binding","volume":"21","author":"Kusano","year":"2012","journal-title":"Protein Sci."}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/11\/5\/788\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:16:13Z","timestamp":1760138173000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/11\/5\/788"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,21]]},"references-count":33,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["biology11050788"],"URL":"https:\/\/doi.org\/10.3390\/biology11050788","relation":{},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,21]]}}}