Glucose-Regulated Protein 78, via Releasing β-Catenin from Adherens Junctions, Facilitates Its Interaction with STAT3 in Mediating Retinal Neovascularization

Retinopathy due to neovascularization is one of the major causes of vision loss. To understand the mechanisms underlying retinal neovascularization the oxygen-induced retinopathy (OIR) model was used. Two-dimensional gel matrix-assisted laser desorption/ionization time-of-flight/time-of-flight analysis of normoxic and 24-hour post-OIR mice pups' retinas revealed that glucose-regulated protein 78 (GRP78) was one of the several molecules induced by OIR in the retinal endothelial cells (ECs). Vascular endothelial growth factor A (VEGFA) also induced GRP78 expression independent of endoplasmic reticulum stress response in human retinal microvascular endothelial cells, and its depletion reduced VEGFA-induced EC angiogenic responses. Consistent with these observations, EC-specific deletion of GRP78 inhibited OIR-induced retinal neovascularization. GRP78 bound with vascular endothelial–cadherin and released adherens junction, but not Wnt-mediated, β-catenin. β-catenin, in turn, via interacting with STAT3, triggered cyclin D1 expression. Furthermore, depletion of β-catenin or cyclin D1 levels negated VEGFA-induced EC angiogenic responses and OIR-induced retinal neovascularization. EC-specific deletion of GRP78 also suppressed OIR-induced vascular leakage. Studies of upstream signaling indicated that activating transcription factor 6 mediated GRP78 induction in the modulation of VEGFA-induced EC angiogenic responses and OIR-induced retinal neovascularization. Together, these observations revealed that GRP78, independent of its response to endoplasmic reticulum stress, is involved in mediating EC angiogenic responses by VEGFA and retinal neovascularization by OIR. In view of these findings, GRP78 emerges as a desirable target for drug development against diabetic retinopathy.