期刊
AMERICAN JOURNAL OF PATHOLOGY
卷 182, 期 6, 页码 2380-2390出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2013.02.015
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资金
- Cabinet Office, Government of Japan
- JSPS KAKENHI [23390400]
- PRESTO of the Japan Science and Technology Agency (JST)
- Ministry of Education, Culture, Sports, Science and Technology
- National Cardiovascular Center
- Mitsui Life Social Welfare Foundation
- Takeda Science Foundation
- Kanzawa Medical Research Foundation
- Public Trust Fund for the Promotion of Surgery
- Suzuken Memorial Foundation
- Japan Heart Foundation
- Naito Foundation
- SENSHIN Medical Research Foundation
- NOVARTIS Foundation (Japan) for the Promotion of Science
- Grants-in-Aid for Scientific Research [23790288, 23390400, 25460330] Funding Source: KAKEN
Adrenomedullin (ADM) is an endogenous peptide first identified as a strong vasodilating molecule. We previously showed that in mice, homozygous knockout of ADM (ADM(-/-)) or its receptor regulating protein, RAMP2 (RAMP2(-/-)), is embryonically lethal due to abnormal vascular development, thereby demonstrating the importance of ADM and its receptor signaling to vascular development. ADM expression in the retina is strongly induced by ischemia; however, its role in retinal pathophysiology remains unknown. Here, we analyzed oxygen-induced retinopathy (OIR) using heterozygous ADM and RAMP2 knockout mice models (ADM(+/-) or RAMP2(+/-) respectively). In addition, we analyzed the role of the ADM-RAMP2 system during earlier stages of retinal angiogenesis using an inducible endothelial cell-specific RAMP2 knockout mouse Line (DI-E-RAMP2(-/-)). Finally, we assessed the ability of antibody-induced ADM blockade to control pathological retinal angiogenesis in OIR. In OIR, neovascular tufts, avascular zones, and hypoxic areas were all smaller in ADM(+/-) retinas compared with wild-type mice. ADM+/- retinas also exhibited reduced levels of VEGF and eNOS expression. DI-E-RAMP2-/- showed abnormal retinal vascular patterns in the early stages of development. However, ADM enhanced the proliferation and migration of retinal endothelial cells. Finally, we found intravitreal injection of anti-ADM antibody reduced pathological retinal angiogenesis. In conclusion, the ADM-RAMP2 system is crucially involved in retinal angiogenesis. ADM and its receptor system are potential therapeutic targets for controlling pathological retinal angiogenesis.
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