Abstract
Inflammatory cytokines and growth factors drive angiogenesis independently; however, their integrated role in pathologic and physiologic angiogenesis is not fully understood. Suppressor of cytokine signaling-3 (SOCS3) is an inducible negative feedback regulator of inflammation and growth factor signaling. In the present study, we show that SOCS3 curbs pathologic angiogenesis. Using a Cre/Lox system, we deleted SOCS3 in vessels and studied developmental and pathologic angiogenesis in murine models of oxygen-induced retinopathy and cancer. Conditional loss of SOCS3 leads to increased pathologic neovascularization, resulting in pronounced retinopathy and increased tumor size. In contrast, physiologic vascularization is not regulated by SOCS3. In vitro, SOCS3 knockdown increases proliferation and sprouting of endothelial cells costimulated with IGF-1 and TNFα via reduced feedback inhibition of the STAT3 and mTOR pathways. These results identify SOCS3 as a pivotal endogenous feedback inhibitor of pathologic angiogenesis and a potential therapeutic target acting at the converging crossroads of growth factor- and cytokine-induced vessel growth.
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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Blotting, Western
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Carcinoma, Lewis Lung / blood supply
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Carcinoma, Lewis Lung / pathology
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Carcinoma, Lewis Lung / prevention & control*
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Cell Proliferation
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Endothelium, Vascular / cytology
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Endothelium, Vascular / metabolism
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Hypoxia / pathology*
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Insulin-Like Growth Factor I / genetics
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Insulin-Like Growth Factor I / metabolism
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Integrases / metabolism
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Male
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Melanoma, Experimental / blood supply
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Melanoma, Experimental / pathology
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Melanoma, Experimental / prevention & control*
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Mice
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Mice, Inbred C57BL
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Neovascularization, Pathologic / etiology
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Neovascularization, Pathologic / prevention & control*
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Paraneoplastic Syndromes, Ocular / pathology
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Paraneoplastic Syndromes, Ocular / prevention & control*
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RNA, Messenger / genetics
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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STAT3 Transcription Factor / genetics
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STAT3 Transcription Factor / metabolism
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Signal Transduction
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins / physiology*
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / metabolism
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism
Substances
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RNA, Messenger
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STAT3 Transcription Factor
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Socs3 protein, mouse
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Stat3 protein, mouse
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Tumor Necrosis Factor-alpha
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Insulin-Like Growth Factor I
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mTOR protein, mouse
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TOR Serine-Threonine Kinases
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Cre recombinase
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Integrases