title: Single and Compound Knock-outs of MicroRNA (miRNA)-155 and Its Angiogenic Gene Target CCN1 in Mice Alter Vascular and Neovascular Growth in the Retina via Resident Microglia.
abstract: The response of the retina to ischemic insult typically leads to aberrant retinal neovascularization, a major cause of blindness. The epigenetic regulation of angiogenic gene expression by miRNAs provides new prospects for their therapeutic utility in retinal neovascularization. Here, we focus on miR-155, a microRNA functionally important in inflammation, which is of paramount importance in the pathogenesis of retinal neovascularization. Whereas constitutive miR-155-deficiency in mice results in mild vascular defects, forced expression of miR-155 causes endothelial hyperplasia and increases microglia count and activation. The mouse model of oxygen-induced retinopathy, which recapitulates ischemia-induced aberrant neovessel growth, is characterized by increased expression of miR-155 and localized areas of microglia activation. Interestingly, miR-155 deficiency in mice reduces microglial activation, curtails abnormal vessel growth, and allows for rapid normalization of the retinal vasculature following ischemic insult. miR-155 binds to the 3'-UTR and represses the expression of the CCN1 gene, which encodes an extracellular matrix-associated integrin-binding protein that both promotes physiological angiogenesis and harnesses growth factor-induced abnormal angiogenic responses. Single CCN1 deficiency or double CCN1 and miR-155 knock-out in mice causes retinal vascular malformations typical of faulty maturation, mimicking the vascular alterations of miR-155 gain of function. During development, the miR-155/CCN1 regulatory axis balances the proangiogenic and proinflammatory activities of microglia to allow for their function as guideposts for sprout fusion and anastomosis. Under ischemic conditions, dysregulated miR-155 and CCN1 expression increases the inflammatory load and microglial activation, prompting aberrant angiogenic responses. Thus, miR-155 functions in tandem with CCN1 to modulate inflammation-induced vascular homeostasis and repair.
authors.affiliation: From the Departments of Cell Biology.
authors.forename: Lulu
authors.initials: L
authors.lastname: Yan
authors.affiliation: From the Departments of Cell Biology.
authors.forename: Sangmi
authors.initials: S
authors.lastname: Lee
authors.affiliation: Ophthalmology, and.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Lazzaro
authors.affiliation: Pediatrics, College of Medicine, and.
authors.forename: Jacob
authors.initials: J
authors.lastname: Aranda
authors.affiliation: the Departments of Ophthalmology and Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors.forename: Maria B
authors.initials: MB
authors.lastname: Grant
authors.affiliation: From the Departments of Cell Biology, Ophthalmology, and the SUNY Eye Institute, SUNY Downstate Medical Center, Brooklyn, New York 11203 and bchaqour@downstate.edu.
authors.forename: Brahim
authors.initials: B
authors.lastname: Chaqour
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D055515:Cysteine-Rich Protein 61 / Q000235:genetics / Q000378:metabolism*; D007511:Ischemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D012160:Retina / Q000378:metabolism* / Q000473:pathology; D015861:Retinal Neovascularization / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012171:Retinal Vessels / Q000378:metabolism* / Q000473:pathology
chemical_list: D020413:3' Untranslated Regions; C491850:CCN1 protein, mouse; D055515:Cysteine-Rich Protein 61; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse
keywords: angiogenesis; extracellular matrix protein; inflammation; microRNA (miRNA); retina