Feb 8th

Role of adrenomedullin-2/intermedin in the pathogenesis of neovascular age-related macular degeneration

Shinji Kakihara1,2, Yorishige Matsuda1,2, Kazutaka Hirabayashi1,2, Akira Imai1,2, Yasuhiro Iesato1,2, Takayuki Sakurai1, Akiko Kamiyoshi1, Megumu Tanaka1, Yuka Ichikawa-Shindo1, Hisaka Kawate1, Yunlu Zhao1, Yan Zhang1, QianQian Guo1, Pexiuan Li1, Naho Onishi1, Toshinori Murata2, Takayuki Shindo1

1 Department of Cardiovascular Research, Shinshu University School of Medicine

2 Department of Ophthalmology, Shinshu University School of Medicine

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Adrenomedullin-2 (AM2; also known as intermedin) is a member of the family peptide of adrenomedullin (AM) which has been reported to exert protective effects on the cardiovascular system. In this study, we generated AM2 knockout mice (AM2-/-) and analyzed the significance of AM2 in pathological angiogenesis in the eye. Pathological retinal angiogenesis in oxygen-induced retinopathy and physiological retinal angiogenesis did not differ between AM2-/- and wild-type mice. In laser-induced choroidal neovascularization (LI-CNV), a model of neovascular age-related macular degeneration (nAMD), AM2-/- had enlarged and leakier vascular lesions with exacerbated subretinal fibrosis and macrophage infiltration. Contrary to this, the exogenous administration of AM2 ameliorated LI-CNV-associated pathologies and suppressed gene expression associated with inflammation, fibrosis, and oxidative stress. The stimulation of human retinal pigment epithelial ARPE-19 cells with TGF-β2 and TNF-α induced epithelial to mesenchymal transition (EMT), while AM2 expression was also elevated. The induction of EMT was suppressed when the ARPE-19 cells were pre-treated with AM2. A transcriptome analysis identified 15 genes, including Meox2, whose expression was significantly altered in the AM2-treated group compared to that in the control group. The expression of Meox2, a transcription factor that inhibits inflammation and fibrosis, was enhanced by AM2 treatment and attenuated by endogenous AM2 knockout in the early phase after laser irradiation. The AM2 treatment of endothelial cells inhibited endothelial to mesenchymal transition (EndMT) and NF-κB activation, but this effect was canceled following Meox2 gene knockdown. These results indicate that AM2 suppresses nAMD-related pathologies partially via the upregulation of Meox2. Thus, AM2 may be a promising therapeutic target for regulating nAMD.