Department of Medicine, Hematology Division, Stanford University, Stanford, CA 94305, USA.
Science. 2010 Nov 12;330(6006):985-9. doi: 10.1126/science.1196554.
The orphan G protein-coupled receptor (GPCR) GPR124/tumor endothelial marker 5 is highly expressed in central nervous system (CNS) endothelium. Here, we show that complete null or endothelial-specific GPR124 deletion resulted in embryonic lethality from CNS-specific angiogenesis arrest in forebrain and neural tube. Conversely, GPR124 overexpression throughout all adult vascular beds produced CNS-specific hyperproliferative vascular malformations. In vivo, GPR124 functioned cell-autonomously in endothelium to regulate sprouting, migration, and developmental expression of the blood-brain barrier marker Glut1, whereas in vitro, GPR124 mediated Cdc42-dependent directional migration to forebrain-derived, vascular endothelial growth factor-independent cues. Our results demonstrate CNS-specific angiogenesis regulation by an endothelial receptor and illuminate functions of the poorly understood adhesion GPCR subfamily. Further, the functional tropism of GPR124 marks this receptor as a therapeutic target for CNS-related vascular pathologies.
孤儿 G 蛋白偶联受体 (GPCR) GPR124/肿瘤内皮标志物 5 在中枢神经系统 (CNS) 内皮中高度表达。在这里，我们表明完全缺失或内皮特异性 GPR124 缺失会导致前脑和神经管中 CNS 特异性血管生成停滞而导致胚胎致死。相反，整个成年血管床中的 GPR124 过表达会导致 CNS 特异性增殖性血管畸形。在体内，GPR124 在血管内皮中自主发挥作用，调节芽生、迁移和血脑屏障标志物 Glut1 的发育表达，而在体外，GPR124 介导 Cdc42 依赖性向脑源性、血管内皮生长因子非依赖性信号的定向迁移。我们的研究结果表明，内皮受体可特异性调节 CNS 血管生成，并阐明了这一尚未充分了解的粘附 GPCR 亚家族的功能。此外，GPR124 的功能倾向将该受体标记为 CNS 相关血管病变的治疗靶点。
