SOCS3 is an endogenous inhibitor of pathologic angiogenesis

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. IntroductionPhysiologic angiogenesis is tightly regulated. However, in proliferative retinopathy and cancer, there is excessive and disorganized growth of pathologic blood vessels. We hypothesized that there are endogenous angiostatic regulators that restrain pathologic vascular growth triggered by massive inflammatory and growth factor angiogenic stimuli. In the present study, we examined suppressor of cytokine signaling-3 (SOCS3) as such an endogenous angiostatic regulator.SOCS proteins are known negative feedback regulators of inflammation and growth factor signaling. 1,2 SOCS3 is transiently induced by inflammatory mediators such as lipopolysaccharide, 3 IL-6, 3 and TNF␣. 4 SOCS3 inhibits cytoplasmic effectors such as the JAK/STAT kinases and deactivates tyrosine kinase receptor signaling, including the IGF-1 receptor. 1,5 It also regulates endothelial cell (EC) apoptosis. 4 However, the role of SOCS3 in regulating angiogenesis in vivo is unknown. If SOCS3 were angiostatic, as has been hypothesized, then its suppression would increase neovascularization in pathologic conditions (see Figure 1A).Systemic deletion of Socs3 is embryonically lethal. 6,7 Therefore, in the present study, we generated Tie2-specific conditional Socs3 knock-out mice (Tie2-Socs3 ko ) 8 to compare developmental and pathologic angiogenic responses with littermate controls (Socs3 flox/flox ). In oxygen-induced retinopathy (OIR), 9-12 which mimics proliferative retinopathy, and in 2 tumor models, vascular deletion of Socs3 increased pathologic angiogenesis. Lack of SOCS3-mediated suppression of STAT3 and mTOR activation promoted EC proliferation and vascular sprouting. SOCS3 is therefore a newly identified endogenous negative regulator of angiogenesis acting on both inflammation and growth factormediated vessel formation specifically in pathologic contexts. Methods Animal modelsExperiments adhered to the National Institutes of Health Guide for the Care and Use of Laboratory Animals 13 and were approved by the Boston Children's Hospital Animal Care and Use Committee. Tie2-Cre-expressing C57Bl/6 mice were crossed with Socs3 flox/flox mice (Dr Yoshimura, Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan 14 ) to generate Tie2-Socs3 ko and littermate control mice (Socs3 flox/flox ). In OIR, mice were exposed to 75% oxygen from P7-12. Retinas were dissected at the disease peak (postnatal day 17 [P17]) and neovascularization analyzed using SWIFT_NV. 15 Mice Ͻ 5 g (P17) ...

Nuclear receptor RORα regulates pathologic retinal angiogenesis by modulating SOCS3-dependent inflammation

“…RORα suppression of Socs3 promoted retinal inflammation, consistent with previous reports showing increased inflammation in Socs3-deficient macrophages in myeloid-specific Socs3 knockout mice (28). Depletion of Socs3 in Tie2-expressing cells also promoted pathologic neovascularization in OIR (42), reflecting an endogenous inhibitory role of SOCS3 in blood vessels. Low levels or transient induction of RORα in the endothelium may also potentially mediate endothelial SOCS3-dependent inflammation.…”

Indoleamine 2,3-Dioxygenase and Its Therapeutic Inhibition in Cancer

“…However, since overall metastatic tumor outgrowth in Ido1 −/− mice was also significantly reduced, it was not clear if the reduction blood vessel formation was a direct effect of IDO1 loss. To test the idea that IDO1 is important for supporting neovascularization outside other possible confounding effects within the tumor microenvironment, studies were conducted in a mouse OIR (oxygen-induced retinopathy) model, a well established, reproducibly quantifiable surrogate system for studying neovascularization (Palmer et al , 2012; Stahl et al , 2012). As predicted, Ido1 −/− mice exhibited a significant reduction in OIR-induced retinal neovascularization relative to their WT counterparts (Mondal et al, 2016).…”

Calpastatin Counteracts Pathological Angiogenesis by Inhibiting Suppressor of Cytokine Signaling 3 Degradation in Vascular Endothelial Cells

“…3 Interestingly, inflammatory and angiogenic signals are slightly interrelated and redundant. Indeed, several classes of proinflammatory cytokines, including tumor necrosis factor-α 4,5 and interleukin (IL)-6, 6 have angiogenic effects on vascular endothelial cells (ECs).…”

“…7 Furthermore, ablation of endothelial suppressor of cytokine signaling 3 (SOCS3), an endogenous inhibitor of JAK/STAT signals, reportedly accelerates growth factor-induced angiogenesis and cytokine-induced angiogenesis, thereby aggravating cancer growth and oxygen-induced retinopathy (OIR) in mice. 5 Thus, it is considered that JAK/STAT/SOCS signals play a pivotal role in pathological angiogenesis under the inflammatory conditions.…”