title: Functional differentiation of RAMP2 and RAMP3 in their regulation of the vascular system.
abstract: Adrenomedullin (AM) is a vasoactive peptide that possesses various bioactivities. AM receptors are dimers consisting of CLR with one of two accessory proteins, RAMP2 or RAMP3. The functional difference between CLR/RAMP2 and CLR/RAMP3 and the relationship between the two receptors remain unclear. To address these issues, we generated RAMP2 and RAMP3 knockout (-/-) mice and have been studying their physiological activities in the vascular system. AM-/- and RAMP2-/- mice die in utero due to blood vessel abnormalities, which is indicative of their essential roles in vascular development. In contrast, RAMP3-/- mice were born normally without any major abnormalities. In adult RAMP3-/- mice, postnatal angiogenesis was normal, but lymphangiography using indocyanine green (ICG) showed delayed drainage of subcutaneous lymphatic vessels. Moreover, chyle transport by intestinal lymphatics was delayed in RAMP3-/- mice, which also showed more severe interstitial edema than wild-type mice in a tail lymphedema model, with characteristic dilatation of lymphatic capillaries and accumulation of inflammatory cells. In scratch-wound assays, migration of isolated RAMP3-/- lymphatic endothelial cells was delayed as compared to wild-type cells, and AM administration failed to enhance the re-endothelialization. The delay in re-endothelialization was due to a primary migration defect rather than a decrease in proliferation. These results suggest that RAMP3 regulates drainage through lymphatic vessels, and that the AM-RAMP3 system could be a novel therapeutic target for controlling postoperative lymphedema.
authors.affiliation: Department of Cardiovascular Disease, Shinshu University Graduate School of Medicine, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yamauchi
authors.affiliation: Department of Cardiovascular Disease, Shinshu University Graduate School of Medicine, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Sakurai
authors.affiliation: Department of Cardiovascular Disease, Shinshu University Graduate School of Medicine, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Kamiyoshi
authors.affiliation: Department of Cardiovascular Disease, Shinshu University Graduate School of Medicine, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Ichikawa-Shindo
authors.affiliation: Department of Cardiovascular Disease, Shinshu University Graduate School of Medicine, Japan.
authors.forename: Hisaka
authors.initials: H
authors.lastname: Kawate
authors.affiliation: Department of Cardiovascular Disease, Shinshu University Graduate School of Medicine, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Igarashi
authors.affiliation: Department of Cardiovascular Disease, Shinshu University Graduate School of Medicine, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Toriyama
authors.affiliation: Department of Cardiovascular Disease, Shinshu University Graduate School of Medicine, Japan.
authors.forename: Megumu
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Department of Cardiovascular Disease, Shinshu University Graduate School of Medicine, Japan.
authors.forename: Tian
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Cardiovascular Disease, Shinshu University Graduate School of Medicine, Japan.
authors.forename: Xian
authors.initials: X
authors.lastname: Xian
authors.affiliation: Department of Cardiovascular Disease, Shinshu University Graduate School of Medicine, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Imai
authors.affiliation: Department of Cardiovascular Disease, Shinshu University Graduate School of Medicine, Japan.
authors.forename: Liuyu
authors.initials: L
authors.lastname: Zhai
authors.affiliation: Department of Cardiovascular Disease, Shinshu University Graduate School of Medicine, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Owa
authors.affiliation: Department of Cardiovascular Disease, Shinshu University Graduate School of Medicine, Japan.
authors.forename: Takuma
authors.initials: T
authors.lastname: Arai
authors.affiliation: Department of Cardiovascular Disease, Shinshu University Graduate School of Medicine, Japan. Electronic address: tshindo@shinshu-u.ac.jp.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Shindo
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004729:Endothelium, Lymphatic / Q000378:metabolism / Q000473:pathology; D005260:Female; D005804:Genes, Lethal; D006614:Hindlimb / Q000098:blood supply; D007511:Ischemia / Q000235:genetics / Q000378:metabolism; D008209:Lymphedema / Q000235:genetics / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D058263:Receptor Activity-Modifying Protein 2 / Q000235:genetics* / Q000378:metabolism; D058264:Receptor Activity-Modifying Protein 3 / Q000235:genetics* / Q000378:metabolism
chemical_list: C545506:Ramp2 protein, mouse; C545507:Ramp3 protein, mouse; D058263:Receptor Activity-Modifying Protein 2; D058264:Receptor Activity-Modifying Protein 3
keywords: Adrenomedullin (AM); Angiogenesis; Knockout mice; Lymphatic drainage; Receptor activity-modifying protein (RAMP)