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Jean-Sebastien Joyal, Andreas Stahl, Ye Sun, Zhuo Shao, Zhongjie Fu, Aimee Juan, Dorothy Pei, Christian Hurst, Jing Chen, Lois Smith; SOCS3 inhibits pathologic angiogenesis. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5574.
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Massive upregulation of inflammatory mediators and growth factors drive pathologic angiogenesis whereas physiologic angiogenesis is more controlled. SOCS3 is an inducible negative feedback regulator acting downstream of both cytokines and growth factor signaling. We hypothesized that SOCS3 might act as an endogenous angiostatic to modulate pathological blood vessel growth.
Using a Cre/Lox system, we deleted SOCS3 in vessels and studied developmental and pathologic angiogenesis in murine models of oxygen-induced retinopathy (OIR) 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 co-stimulated with EPO and TNFα via reduced feedback inhibition of the STAT3 and mTOR pathways. Reintroducing SOCS3 curbs tumor growth and pathologic angiogenesis.
These results identify SOCS3 as a pivotal endogenous feedback inhibitor of angiogenesis that is specifically induced in pathologic states, but not in physiologic angiogenesis. Acting at the converging crossroads of growth factor- and cytokine-induced angiogenesis, SOCS3 is a potential therapeutic target to treat angiogenic disorders like proliferative retinopathies and cancer.
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