{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T05:02:54Z","timestamp":1784264574033,"version":"3.55.0"},"reference-count":57,"publisher":"The Endocrine Society","issue":"3","license":[{"start":{"date-parts":[[2021,1,6]],"date-time":"2021-01-06T00:00:00Z","timestamp":1609891200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"JSPS KAKENHI","award":["18KT0005"],"award-info":[{"award-number":["18KT0005"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Adrenomedullin (AM) is a peptide hormone with multiple physiological functions, which are regulated by its receptor activity\u2013modifying proteins, RAMP2 and RAMP3. We previously reported that AM or RAMP2 knockout (KO) (AM\u2013\/\u2013, RAMP2\u2013\/\u2013) is embryonically lethal in mice, whereas RAMP3\u2013\/\u2013 mice are apparently normal. AM, RAMP2, and RAMP3 are all highly expressed in the heart; however, their functions there are not fully understood. Here, we analyzed the pathophysiological functions of the AM-RAMP2 and AM-RAMP3 systems in hearts subjected to cardiovascular stress. Cardiomyocyte-specific RAMP2\u2013\/\u2013 (C-RAMP2\u2013\/\u2013) and RAMP3\u2013\/\u2013 showed no apparent heart failure at base line. After 1 week of transverse aortic constriction (TAC), however, C-RAMP2\u2013\/\u2013 exhibited significant cardiac hypertrophy, decreased ejection fraction, and increased fibrosis compared with wild-type mice. Both dP\/dtmax and dP\/dtmin were significantly reduced in C-RAMP2\u2013\/\u2013, indicating reduced ventricular contractility and relaxation. Exposing C-RAMP2\u2013\/\u2013 cardiomyocytes to isoproterenol enhanced their hypertrophy and oxidative stress compared with wild-type cells. C-RAMP2\u2013\/\u2013 cardiomyocytes also contained fewer viable mitochondria and showed reduced mitochondrial membrane potential and respiratory capacity. RAMP3\u2013\/\u2013 also showed reduced systolic function and enhanced fibrosis after TAC, but those only became apparent after 4 weeks. A reduction in cardiac lymphatic vessels was the characteristic feature in RAMP3\u2013\/\u2013. These observations indicate the AM-RAMP2 system is necessary for early adaptation to cardiovascular stress through regulation of cardiac mitochondria. AM-RAMP3 is necessary for later adaptation through regulation of lymphatic vessels. The AM-RAMP2 and AM-RAMP3 systems thus play separate critical roles in the maintenance of cardiovascular homeostasis against cardiovascular stress.<\/jats:p>","DOI":"10.1210\/endocr\/bqab001","type":"journal-article","created":{"date-parts":[[2021,1,10]],"date-time":"2021-01-10T22:39:09Z","timestamp":1610318349000},"source":"Crossref","is-referenced-by-count":15,"title":["Adrenomedullin-RAMP2 and -RAMP3 Systems Regulate Cardiac Homeostasis during Cardiovascular Stress"],"prefix":"10.1210","volume":"162","author":[{"given":"Nanqi","family":"Cui","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayuki","family":"Sakurai","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto, Japan"},{"name":"Department of Life Innovation, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiko","family":"Kamiyoshi","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto, Japan"},{"name":"Department of Life Innovation, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto, 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, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisaka","family":"Kawate","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto, 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Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsutomu","family":"Nakada","sequence":"additional","affiliation":[{"name":"Department of Instrumental Analysis, Research Center for Supports to Advanced Science, Shinshu University, Matsumoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuhiko","family":"Yamada","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology, Shinshu University School of Medicine, Matsumoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1262-0819","authenticated-orcid":false,"given":"Takayuki","family":"Shindo","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto, Japan"},{"name":"Department of Life Innovation, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto, 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