Abstract
Oxygen-induced retinopathy (OIR) is a well-characterized model for retinopathy of prematurity, a disorder that results from rapid microvascular proliferation after exposure of the retina to high oxygen levels. Here, we report that the proliferative phase of OIR requires transcriptional induction of the annexin A2 (A2) gene through the direct action of the hypoxia-inducible factor-1 complex. We show, in addition, that A2 stabilizes its binding partner, p11, and promotes OIR-related angiogenesis by enabling clearance of perivascular fibrin. Adenoviral-mediated restoration of A2 expression restores neovascularization in the oxygen-primed Anxa2(-/-) retina and reinstates plasmin generation and directed migration in cultured Anxa2(-/-) endothelial cells. Systemic depletion of fibrin repairs the neovascular response to high oxygen treatment in the Anxa2(-/-) retina, whereas inhibition of plasminogen activation dampens angiogenesis under the same conditions. These findings show that the A2 system enables retinal neoangiogenesis in OIR by enhancing perivascular activation of plasmin and remodeling of fibrin. These data suggest new potential approaches to retinal angiogenic disorders on the basis of modulation of perivascular fibrinolysis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Annexin A2 / physiology*
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Aorta / cytology
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Aorta / metabolism
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Blotting, Western
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Cell Movement
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Cells, Cultured
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Chromatin Immunoprecipitation
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Electrophoretic Mobility Shift Assay
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Endothelium, Vascular / cytology
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Endothelium, Vascular / metabolism
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Enzyme-Linked Immunosorbent Assay
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Fibrin / metabolism*
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Fibrinolysin / metabolism
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Fibrinolysis
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Flow Cytometry
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Gene Expression Regulation
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Humans
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Hypoxia
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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Immunoenzyme Techniques
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Immunoprecipitation
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Luciferases / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Neovascularization, Pathologic*
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Oxygen / adverse effects*
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Plasminogen Activators / metabolism
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Promoter Regions, Genetic / genetics
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RNA Stability
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RNA, Messenger / genetics
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Retinal Diseases / etiology*
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Retinal Diseases / metabolism*
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Retinal Diseases / pathology
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Reverse Transcriptase Polymerase Chain Reaction
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Transfection
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Umbilical Veins / cytology
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Umbilical Veins / metabolism
Substances
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Annexin A2
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Hif1a protein, mouse
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Hypoxia-Inducible Factor 1, alpha Subunit
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RNA, Messenger
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Fibrin
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Luciferases
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Plasminogen Activators
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Fibrinolysin
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Oxygen