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

被引：227

作者：

Kuhnert, Frank ^{[1
]}

Mancuso, Michael R. ^{[1
]}

Shamloo, Amir ^{[2
]}

Wang, Hsiao-Ting ^{[1
]}

Choksi, Vir ^{[3
]}

Florek, Mareike ^{[4
]}

Su, Hua

Fruttiger, Marcus ^{[5
]}

Young, William L. ^{[6
]}

Heilshorn, Sarah C. ^{[7
]}

Kuo, Calvin J. ^{[1
]}

机构：

[1] Stanford Univ, Dept Med, Div Hematol, Stanford, CA 94305 USA

[2] Stanford Univ, Dept Mech Engn, Stanford, CA 94305 USA

[3] Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA

[4] Stanford Univ, Div Blood & Marrow Transplantat, Stanford, CA 94305 USA

[5] UCL, UCL Inst Ophthalmol, London EC1V 9EL, England

[6] Univ Calif San Francisco, Dept Neurol Surg, Ctr Cerebrovasc Res, Dept Anesthesia & Perioperat Care,Dept Neurol, San Francisco, CA 94110 USA

[7] Stanford Univ, Dept Mat Sci & Engn, Stanford, CA 94305 USA

来源：

SCIENCE | 2010年 / 330卷 / 6006期

基金：

英国医学研究理事会;

关键词：

CENTRAL-NERVOUS-SYSTEM; BLOOD-BRAIN-BARRIER; ALPHA-V INTEGRINS; INACTIVATION; ENDOTHELIUM; LETHALITY; GENE; MICE; NEUROGENESIS; HEMORRHAGE;

D O I：

10.1126/science.1196554

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：985 / 989

页数：5

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