期刊
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
卷 77, 期 -, 页码 73-85出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.yjmcc.2014.09.017
关键词
Receptor activity-modifying protein (RAMP); Adrenomedullin (AM); Knockout mice; Angiogenesis; Lymphatic drainage
资金
- Cabinet Office, Government of Japan [LS053]
- KAKENHI [26293183, 26293085, 25460330, 26460337]
- National Cardiovascular Center
- Novartis Foundation for Gerontological Research
- Ichiro Kanehara Foundation
- Cosmetology Research Foundation
- SENSHIN Medical Research Foundation
- Nagao Memorial Fund
- Kanzawa Medical Research Foundation
- Ono Medical Research Foundation
- Nakatomi Foundation
- Japan Heart Foundation & Astellas/Pfizer Grant for Research on Atherosclerosis Update
- Research Foundation for Opto-Science and Technology
- Japan Vascular Disease Research Foundation
- Takeda Science Foundation
- Grants-in-Aid for Scientific Research [25460330, 26293085, 26293183] Funding Source: KAKEN
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. (C) 2014 Elsevier Ltd. All rights reserved.
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