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J. Li, J. J. Wang, Q. Yu, S. X. Zhang; XBP1 Suppresses Pathological Retinal Neovascularization via Inhibition of Integrin β3 and VEGF Pathways. Invest. Ophthalmol. Vis. Sci. 2010;51(13):6384.
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© ARVO (1962-2015); The Authors (2016-present)
Aberrant neovascularization (NV) is a major cause of blindness in ischemic retinal diseases, such as diabetic retinopathy and oxygen-induced retinopathy (OIR). Our previous study demonstrates that endoplasmic reticulum (ER) stress and ER stress-triggered cellular adaptive response, so-called the unfolded protein response (UPR), are activated in the retina of OIR mice. X-box binding protein 1 (XBP1) is a master coordinator of the UPR, governing cellular response to ER stress. XBP1 is expressed in vascular endothelial cells; however, the role of XBP1 in endothelial function and angiogenesis remains largely unknown. The purpose of this study is to determine the function and mechanisms of XBP1 in the development of retinal NV.
OIR was induced by exposure of neonatal C57 mice from postnatal day 7 (P7) to P12 followed by room air. Expression of XBP1 in the retina was determined during the development of retinal NV. A separate group of animals received intravitreal injection of adenovirus expressing active XBP1 (Ad-XBP1-S) or GFP (Ad-GFP) as control at P12. Mice were sacrificed at P17 and retinal NV was assessed by staining of flat-mount with isolectin. Primary human retinal microvascular endothelial cells (HREC) were used for in vitro study. Matrigel angiogenesis, transwell migration and wound healing, and Click-iT EdU assay were used to evaluate endothelial angiogenic capacity, migration, and proliferation, respectively. Expression of Intergrin β3, phosphorylation of VEGF receptor2 (VEGFR2), and activation of the MAPK pathway were also determined.
Expression of active XBP1 (XBP1-S) in retina was significantly increased after hyperoxia treatment at P12, and decreased at P15 during the development of retinal NV in OIR. Intravitreal injection of Ad-XBP1-S significantly reduced retinal NV formation in OIR mice when compared with control eyes. In keeping, over-expression of XBP1-S in cultured HREC attenuated VEGF-induced tube-formation and cell migration or wound healing. Moreover, Ad-XBP1-S significantly decreased endothelial cell proliferation. Exposure of HREC to VEGF induced a rapid phosphorylation of VEGFR2 and activation of the ERK1/2 MAPK pathway, which was abolished in Ad-XBP1-S-treated cells. In addition, over-expression of XBP1-S significantly decreased expression of integrin β3, a critical factor essential for action of VEGF signaling pathway and endothelial cell migration.
Taken together, our data suggest that XBP1-S suppresses retinal endothelial proliferation, migration and angiogenesis, likely through inhibition of integrin β3 and VEGF-mediated signaling pathways.
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