Essential regulation of CNS angiogenesis by the orphan G protein-coupled receptor GPR124

Science. 2010 Nov 12;330(6006):985-9. doi: 10.1126/science.1196554.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Vessels / abnormalities
  • Blood-Brain Barrier / metabolism
  • Cell Movement
  • Embryonic Development
  • Endothelial Cells / physiology
  • Endothelium, Vascular / embryology
  • Endothelium, Vascular / metabolism
  • Gene Deletion
  • Glucose Transporter Type 1 / metabolism
  • Mesencephalon / blood supply
  • Mesencephalon / embryology
  • Mesencephalon / metabolism
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Neovascularization, Physiologic*
  • Neural Tube / blood supply*
  • Neural Tube / embryology
  • Neural Tube / metabolism
  • Prosencephalon / blood supply*
  • Prosencephalon / embryology
  • Prosencephalon / metabolism
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Rhombencephalon / blood supply
  • Rhombencephalon / embryology
  • Rhombencephalon / metabolism
  • Telencephalon / blood supply
  • Telencephalon / embryology
  • Telencephalon / metabolism

Substances

  • GPR124 protein, mouse
  • Glucose Transporter Type 1
  • Receptors, G-Protein-Coupled
  • Slc2a1 protein, mouse