title: Strand and Cell Type-specific Function of microRNA-126 in Angiogenesis.
abstract: microRNAs or miRs have been shown to be pivotal modulators of vascular development. The strand and cell type-specific function of miR-126 in angiogenesis, especially pathological angiogenesis, remains poorly defined. We characterized the retinal vascular phenotype of miR-126-/-mice, and tested the function of miR-126 strands (miR-126-3p and -5p) using in vitro angiogenesis models and a mouse model of neovascular age-related macular degeneration. We found that miR-126 is critical for retinal vascular development but has dual function in pathological angiogenesis. miR-126-/-mice showed defective postnatal retinal vascular development and remodeling, which is partially rescued by genetic knockout of its target gene Spred-1. Surprisingly, either silencing miR-126-3p by LNA-antimiR or overexpressing miR-126-3p by miRNA mimic repressed laser-induced choroidal neovascularization. To dissect the underlying mechanism, we found in endothelial cells, silencing of miR-126-3p repressed angiogenesis, while overexpression of miR-126-5p enhanced angiogenesis. However, in retinal pigment epithelial cells, miR-126-3p repressed vascular endothelial growth factor (VEGF-A) expression via a novel mechanism of regulating αB-Crystallin promoter activity and by directly targeting VEGF-A 3'-untranslated region. These findings provide first genetic evidence that miR-126 is required for the development of different retinal vascular layers, and also uncover a strand and cell type-specific function of miR-126 in ocular pathological angiogenesis.
authors.affiliation: Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana, USA.
authors.forename: Qinbo
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana, USA.
authors.forename: Chastain
authors.initials: C
authors.lastname: Anderson
authors.affiliation: Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana, USA.
authors.forename: Jakub
authors.initials: J
authors.lastname: Hanus
authors.affiliation: Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana, USA.
authors.forename: Fangkun
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
authors.affiliation: Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana, USA.|Department of Ophthalmology, Tulane University, New Orleans, Louisiana, USA.
authors.forename: Shusheng
authors.initials: S
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D049109:Cell Proliferation; D018920:Coculture Techniques; D004195:Disease Models, Animal; D005123:Eye / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008268:Macular Degeneration / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009389:Neovascularization, Pathologic / Q000235:genetics*; D018919:Neovascularization, Physiologic; D009928:Organ Specificity; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; C527111:MIRN126 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; C504812:SPRED1 protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A