Abstract
Endothelial cells play essential roles in maintenance of vascular integrity, angiogenesis, and wound repair. We show that an endothelial cell-restricted microRNA (miR-126) mediates developmental angiogenesis in vivo. Targeted deletion of miR-126 in mice causes leaky vessels, hemorrhaging, and partial embryonic lethality, due to a loss of vascular integrity and defects in endothelial cell proliferation, migration, and angiogenesis. The subset of mutant animals that survives displays defective cardiac neovascularization following myocardial infarction. The vascular abnormalities of miR-126 mutant mice resemble the consequences of diminished signaling by angiogenic growth factors, such as VEGF and FGF. Accordingly, miR-126 enhances the proangiogenic actions of VEGF and FGF and promotes blood vessel formation by repressing the expression of Spred-1, an intracellular inhibitor of angiogenic signaling. These findings have important therapeutic implications for a variety of disorders involving abnormal angiogenesis and vascular leakage.
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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Adaptor Proteins, Signal Transducing
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Animals
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Base Sequence
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Blood Vessels / abnormalities
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Blood Vessels / ultrastructure
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Calcium-Binding Proteins
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EGF Family of Proteins
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Endothelial Cells / metabolism
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Endothelium / blood supply
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Endothelium / metabolism*
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Gene Expression Regulation, Developmental
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Gene Targeting
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Humans
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Intercellular Signaling Peptides and Proteins / metabolism
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Mice
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Mice, Knockout
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MicroRNAs / chemistry
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MicroRNAs / genetics
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MicroRNAs / metabolism*
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Models, Biological
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Molecular Sequence Data
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Myocardial Infarction / pathology
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Neovascularization, Physiologic*
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Organ Specificity
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Proteins / genetics
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Proteins / metabolism
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Regulatory Sequences, Nucleic Acid / genetics
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Repressor Proteins / metabolism
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Signal Transduction
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Survival Analysis
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Transcription, Genetic
Substances
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Adaptor Proteins, Signal Transducing
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Calcium-Binding Proteins
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EGF Family of Proteins
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Egfl7 protein, mouse
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Intercellular Signaling Peptides and Proteins
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MicroRNAs
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Proteins
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Repressor Proteins
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Spred1 protein, mouse