Essential Regulation of CNS Angiogenesis by the Orphan G Protein–Coupled Receptor GPR124

Plumbing in the Brain Superficial similarities of vasculature in different parts of the body may mask organ-specific developmental nuances. The vasculature of the brain uniquely has to insulate the organ from insults that the rest of the body must tolerate. Kuhnert et al. (p. 985) analyzed the developmental uniqueness of the brain's vasculature through study of a G protein–coupled receptor, GPR124, initially identified by its actions in the vasculature of colon cancer. GPR124 is also involved in normal development of the brain's vasculature. Mice expressing low levels of GPR124 did not develop adequate vasculature in the brain and died from hemorrhages. Mice with too much GPR124 developed a tangled, thin-walled, excessive vasculature in the brain. Although the overexpressing mice survived, they were prone to neurological symptoms such as ataxia. GPR124 seems to control the normal development of the endothelial cells, particularly in the forebrain and ventral neural tube. A factor is identified that determines the amount of vasculature in the brain, and, in doing so, affects brain function. 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.

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