title: Inhibition of apelin expression switches endothelial cells from proliferative to mature state in pathological retinal angiogenesis.
abstract: The recruitment of mural cells such as pericytes to patent vessels with an endothelial lumen is a key factor for the maturation of blood vessels and the prevention of hemorrhage in pathological angiogenesis. To date, our understanding of the specific trigger underlying the transition from cell growth to the maturation phase remains incomplete. Since rapid endothelial cell growth causes pericyte loss, we hypothesized that suppression of endothelial growth factors would both promote pericyte recruitment, in addition to inhibiting pathological angiogenesis. Here, we demonstrate that targeted knockdown of apelin in endothelial cells using siRNA induced the expression of monocyte chemoattractant protein-1 (MCP-1) through activation of Smad3, via suppression of the PI3K/Akt pathway. The conditioned medium of endothelial cells treated with apelin siRNA enhanced the migration of vascular smooth muscle cells, through MCP-1 and its receptor pathway. Moreover, in vivo delivery of siRNA targeting apelin, which causes exuberant endothelial cell proliferation and pathological angiogenesis through its receptor APJ, led to increased pericyte coverage and suppressed pathological angiogenesis in an oxygen-induced retinopathy model. These data demonstrate that apelin is not only a potent endothelial growth factor, but also restricts pericyte recruitment, establishing a new connection between endothelial cell proliferation signaling and a trigger of mural recruitment.
authors: Interdisciplinary Program for Biomedical Sciences, Institute for Academic Initiatives, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan. kasai@phs.osaka-u.ac.jp
authors: Atsushi
authors: A
authors: Kasai
authors: Yuki
authors: Y
authors: Ishimaru
authors: Kosuke
authors: K
authors: Higashino
authors: Kohei
authors: K
authors: Kobayashi
authors: Akiko
authors: A
authors: Yamamuro
authors: Yasuhiro
authors: Y
authors: Yoshioka
authors: Sadaaki
authors: S
authors: Maeda
mesh_terms: D054392:Adipokines; D000704:Analysis of Variance; D000818:Animals; D000073861:Apelin; D000075244:Apelin Receptors; D015153:Blotting, Western; D018932:Chemokine CCL2 / Q000378:metabolism*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D055785:Gene Knockdown Techniques; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D012171:Retinal Vessels / Q000503:physiopathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051900:Smad3 Protein / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D054392:Adipokines; D000073861:Apelin; D000075244:Apelin Receptors; C402826:Apln protein, mouse; C491285:Aplnr protein, mouse; D018932:Chemokine CCL2; D017077:Culture Media, Conditioned; D036341:Intercellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D051900:Smad3 Protein; C497791:Smad3 protein, mouse
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