Li Hainan, Xu Liping, Meda Venkata Sai Pranathi, Minjares Morgan, Melhem Hassan, Kowluru Anjaneyulu, Niess Jan Hendrik, Milligan Graeme, Wang Jie-Mei
Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI.
Department of Biomedicine, University of Basel, Basel, Switzerland.
Diabetes. 2025 Jul 1;74(7):1233-1246. doi: 10.2337/db24-0737.
G protein-coupled receptor 35 (GPR35) is a poorly characterized receptor with unclear intracellular mechanisms in endothelial cells (ECs). Oxidative stress responsive kinase 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 ECs from patients with type 2 diabetes (T2D) 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.
Endothelial cell dysfunction is a crucial feature of diabetic wound healing. The underlying molecular mechanisms are poorly understood. We investigated how G protein-coupled receptor 35 (GPR35) inhibition accelerates diabetic wound healing. We found that GPR35 modulated endothelial cell behavior in vitro and identified oxidative stress responsive 1 as its target. Inhibiting GPR35 rescued the healing process in animals with hyperglycemia. This study uncovers novel molecular mechanisms underlying the benefit of GPR35 inhibition on endothelial cell angiogenesis and provides proof-of-concept evidence for therapeutic strategies targeting GPR35 in the endothelium as a potential therapy for diabetic wound care.
G蛋白偶联受体35（GPR35）是一种特征不明的受体，在内皮细胞（ECs）中的细胞内机制尚不清楚。氧化应激反应激酶1（OXSR1）是一种丝氨酸/苏氨酸蛋白激酶，可调节细胞形态，最近发现它能促进血管生成。我们假设，抑制GPR35可通过增强OXSR1活性促进内皮细胞血管生成，并加速糖尿病患者的伤口愈合。在此，我们表明，活性GPR35导致2型糖尿病（T2D）患者的人真皮微血管内皮细胞或暴露于高糖环境的内皮细胞迁移和管腔形成受损。邻近标记和免疫共沉淀确定OXSR1是内皮细胞中GPR35的相互作用伴侣。GPR35抑制OXSR1易位至细胞核以激活SMAD1/5，从而抑制血管生成因子的转录。此外，在局部应用GPR35 siRNA的诱导性T2D小鼠或全身性或内皮细胞选择性GPR35缺失的转基因小鼠T2D模型中，观察到伤口血管生成反应增强和伤口愈合加速。我们的数据表明，GPR35抑制内皮细胞中OXSR1依赖性血管生成活性，导致T2D动物血管生成不良和伤口愈合延迟。这项研究提供了体外和体内证据，证明GPR35作为糖尿病患者组织修复的潜在治疗靶点。
内皮细胞功能障碍是糖尿病伤口愈合的关键特征。其潜在分子机制尚不清楚。我们研究了抑制G蛋白偶联受体35（GPR35）如何加速糖尿病伤口愈合。我们发现GPR35在体外调节内皮细胞行为，并确定氧化应激反应蛋白1为其靶点。抑制GPR35可挽救高血糖动物的愈合过程。这项研究揭示了抑制GPR35对内皮细胞血管生成有益的新分子机制，并为以内皮细胞中GPR35为靶点的治疗策略作为糖尿病伤口护理的潜在疗法提供了概念验证证据。
