G protein-coupled receptor 35 suppresses oxidative stress response 1 in diabetic wound healing.

G protein-coupled receptor 35 (GPR35) is a poorly characterized receptor with unclear intracellular mechanisms in endothelial cells (ECs). Oxidative stress responsive 1 (OXSR1) is a serine/ threonine protein kinase that modulates cell morphology and has recently been found to promote angiogenesis. We hypothesized that GPR35 inhibition promotes EC angiogenesis via augmenting OXSR1 activity and accelerating wound healing in diabetes. Here, we show that active GPR35 contributed to the impaired migration and tube formation of human dermal microvascular endothelial cells (ECs) from type 2 diabetic (T2D) patients or ECs exposed to high glucose. Proximity labeling and coimmunoprecipitation identified OXSR1 as an interacting partner of GPR35 in ECs. GPR35 suppressed OXSR1 from translocating to nuclei to activate SMAD1/5, thereby inhibiting the transcription of angiogenic factors. Furthermore, enhanced wound angiogenic response and accelerated wound closures were observed in induced T2D mice with topical application of GPR35 siRNA, or in T2D models of transgenic mice with either global or endothelial-selective GPR35 deletion. Our data suggest that GPR35 suppresses OXSR1-dependent angiogenic activity in ECs, contributing to poor angiogenesis and delayed wound healing in T2D animals. This study provides both in vitro and in vivo evidence for GPR35 as a potential therapeutic target in tissue repair in patients with diabetes.