SOCS3 attenuates pathologic neovascularization. (A) Schematic representation of SOCS3 functioning as a negative feedback modulator of angiogenic activation. (B-C) Socs3 expression in wild-type mice exposed to OIR compared with normoxia both at the mRNA and protein level (n = 3-4). (D) Socs3 expression is significantly up-regulated in pathologic neovessels obtained by laser microdissection of retinal layers (outlined on the right; n = 4). GCL indicates ganglion cell layer; INL, inner nuclear layer; and ONL, outer nuclear layer. (E) Retinal vasculature of Cre reporter mice Rosa mT^flox/mG. This strain universally expresses a red-fluorescent protein (mT) that is removed in tissues with Cre recombinase expression, revealing instead a green fluorescent protein (mGFP). In control mice, the retinal vasculature is red (top), whereas in Tie2-Cre mice, the retinal vasculature is green (bottom), demonstrating that Tie2-Cre recombinase is expressed in retinal vessels (n = 3). (F) Conditional Tie2-Socs3^ko mice have more pathologic neovascularization in OIR compared with Socs3^flox/flox control mice. The area of vaso-obliteration is unchanged (n = 13-34). (G,I) Increased growth of LLC (G; n = 5-7) and B16F10 melanoma tumors (I; n = 5-9) in Tie2-Socs3^ko compared with Socs3^flox/flox mice. (H,J) Increased tumor vessel density of LLC (H; n = 5-7) and B16F10 melanoma tumors (J; n = 5-9) in Tie2-Socs3^ko compared with Socs3^flox/flox mice. Scale bar in panel E indicates 200 μm; panel F, 1 mm; panels G and I, 1 cm; and in panels H and J, 100 μm. *P < .05, **P < .01, P < .001.