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Kentaro Yuda, Hidenori Takahashi, Tatusya Inoue, Hiroyuki Aburatani, Ryozou Nagai, Yasuhiro Tamaki, Yasuo Yanagi; Adrenomedullin Inhibits Choroidal Neovascularization Via Ccl2 In The Retinal Pigment Epithelium. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4871.
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Adrenomedullin (ADM) is a novel peptide first isolated from human pheochromocytoma. ADM forms complex with complement factor H (CFH), which has been determined to be strongly associated with a person’s risk for developing age-related macular degeneration (AMD), and activates biological activity each other. We examined the effect ADM and choroidal neovascularization (CNV) in mice models and in cells.
(1) To evaluate the effect of ADM on CNV, eyes from ADM+/- mice and age-matched wild-type mice were subjected to laser-induced CNV. Macrophages migrating around CNV were identified by immunostaning for F4/80. (2) In vitro angiogenesis activity was evaluated with the in vitro tube formation assay using Human umbilical vein endothelial cells (HUVEC). Using macrophage cell line (RAW 264.7), we assessed the effects of ADM on macrophage migration in response to secretor factors from D407. (3) The expression of VEGF-A, VEGF-B, CCL2 were examined in D407 stimulated with ADM for 24 hours by real time RT-PCR.
ADM+/- mice showed significant increase in leakage from CNV compared to wild-type mice. F4/80-positive cells were concentrated within the laser burns and around the borders of the laser scars. Increase infiltration with F4/80 positive cells were observed especially in ADM+/- mice in comparison with wild type mice. In vitro experiments using tube formation assay and migration assay, HUVECs cultured with conditioned medium of ADM treated D407 did not inhibit capillary-like tube formation, but RAW264.7 cultured with conditioned medium of ADM treated D407 decreased migration activity. Real-time PCR measuremts demonstrated that whereas VEGF-A and -B showed no change in the expression, CCL2 was significantly inhibited following ADM treatment in D407.
Administration of ADM inhibits the macrophage migration in the subretinal space and lead to suppression of laser-induced CNV in an animal model. This mediated through the CCL2 from RPE, at least in part.
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