title: SOCS3 in retinal neurons and glial cells suppresses VEGF signaling to prevent pathological neovascular growth.
abstract: Neurons and glial cells in the retina contribute to neovascularization, or the formation of abnormal new blood vessels, in proliferative retinopathy, a condition that can lead to vision loss or blindness. We identified a mechanism by which suppressor of cytokine signaling 3 (SOCS3) in neurons and glial cells prevents neovascularization. We found that Socs3 expression was increased in the retinal ganglion cell and inner nuclear layers after oxygen-induced retinopathy. Mice with Socs3 deficiency in neuronal and glial cells had substantially reduced vaso-obliterated retinal areas and increased pathological retinal neovascularization in response to oxygen-induced retinopathy, suggesting that loss of neuronal/glial SOCS3 increased both retinal vascular regrowth and pathological neovascularization. Furthermore, retinal expression of Vegfa (which encodes vascular endothelial growth factor A) was higher in these mice than in Socs3 flox/flox controls, indicating that neuronal and glial SOCS3 suppressed Vegfa expression during pathological conditions. Lack of neuronal and glial SOCS3 resulted in greater phosphorylation and activation of STAT3, which led to increased expression of its gene target Vegfa, and increased endothelial cell proliferation. In summary, SOCS3 in neurons and glial cells inhibited the STAT3-mediated secretion of VEGF from these cells, which suppresses endothelial cell activation, resulting in decreased endothelial cell proliferation and angiogenesis. These results suggest that neuronal and glial cell SOCS3 limits pathological retinal angiogenesis by suppressing VEGF signaling.
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Ye
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Meihua
authors.initials: M
authors.lastname: Ju
authors.affiliation: Department of Cardiology, Harvard Medical School, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Fredrick
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Lucy P
authors.initials: LP
authors.lastname: Evans
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Katherine T
authors.initials: KT
authors.lastname: Tian
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Saba
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Peyton C
authors.initials: PC
authors.lastname: Morss
authors.affiliation: Department of Cardiology, Harvard Medical School, Boston Children's Hospital, Boston, MA 02115, USA. Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors.forename: William T
authors.initials: WT
authors.lastname: Pu
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: University Eye Hospital Freiburg, Killianstr. 5, Freiburg 79106, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Stahl
authors.affiliation: Department of Pediatrics, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Université de Montréal, Montréal, Québec H3T1C4, Canada.
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Joyal
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA. lois.smith@childrens.harvard.edu.
authors.forename: Lois E H
authors.initials: LE
authors.lastname: Smith
mesh_terms: D000818:Animals; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009457:Neuroglia / Q000378:metabolism* / Q000473:pathology; D010100:Oxygen / Q000633:toxicity; D015861:Retinal Neovascularization / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D055351:Retinal Neurons / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D010100:Oxygen