Myeloid precursors develop into endothelial progenitor cells modulated by SOCS3

Abstract

Purpose : Pathological proliferation of blood vessels commonly causes blindness, in age-related macular degeneration, proliferative diabetic retinopathy, or retinopathy of prematurity. Despite an important role in pathological vascular development, the origin of endothelial progenitors remains unknown. We identified a novel factor, suppressor of cytokine signaling 3 (SOCS3), controls myeloid precursor development into endothelial progenitor cells to form vascular endothelium under pathological conditions using mouse models of oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV).

Methods : We used Socs3 knock-out and knock-in mice with Cre/LoxP system. Myeloid specific and endothelial specific Cre mice as well as mT/mG Cre reporter mice were used in OIR and laser-induced CNV mouse models of pathological neovascularization. Real-time PCR, western blot and immunohistochemistry were used to analyze gene expression and protein localization. Confocal imaging, fundus fluorescein angiography and HE staining were used to identify phenotypes. Neovascularization (NV) was quantified using image J. Results are presented as mean ± SEM and were compared using the 2-tailed unpaired t-test. Statistical analyses were performed with GraphPad Prism (v6.0).

Results : Myeloid specific deletion of Socs3 increased pathological NV by 12-15% in OIR (p<0.01, n=10-12) and 30-40% in laser CNV (p<0.001, n=26-30). Myeloid specific overexpression of Socs3 reduced pathological NV by 20 % in OIR (p<0.01, n=10-12) and by ~25% in laser CNV (p<0.001, n=30). These data suggested that myeloid specific Socs3 controls pathological NV in OIR and laser-CNV models. Pathological NV in wild type mice with endothelial specific promoter driven expression of GFP showed no GFP signals in pathological tufts indicating that the origin of pathological tufts was not of endothelial lineage. Pharmacologic treatment with a Socs3 activator suppressed retinal NV in the laser CNV model by 40% (p<0.001, n=45-50) and by 20% in OIR (p<0.01, n=20).

Conclusions : These findings suggested that SOCS3 pathway controls myeloid precursor development into endothelial progenitor cells to form vascular endothelium under pathological conditions.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.