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Molecular and Cellular Biology, February 2007, p. 1334-1347, Vol. 27, No. 4
0270-7306/07/$08.00+0     doi:10.1128/MCB.01909-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Vascular Abnormalities in Mice Deficient for the G Protein-Coupled Receptor GPR4 That Functions as a pH Sensor ^,

Howard Hughes Medical Institute,¹ Department of Molecular and Medical Pharmacology,² Department of Chemistry and Biochemistry,³ Department of Molecular, Cell and Developmental Biology,⁴ Department of Microbiology, Immunology and Molecular Genetics,⁵ Department of Pathology and Laboratory Medicine, University of California—Los Angeles, Los Angeles, California 90095⁶

Received 9 October 2006/ Accepted 25 November 2006

GPR4 is a G protein-coupled receptor expressed in the vasculature, lung, kidney, and other tissues. In vitro ectopic overexpression studies implicated GPR4 in sensing extracellular pH changes leading to cyclic AMP (cAMP) production. To investigate its biological roles in vivo, we generated GPR4-deficient mice by homologous recombination. Whereas GPR4-null adult mice appeared phenotypically normal, neonates showed a higher frequency of perinatal mortality. The average litter size from GPR4^–/– intercrosses was 30% smaller than that from GPR4^+/+ intercrosses on N3 and N5 C57BL/6 genetic backgrounds. A fraction of knockout embryos and neonates had spontaneous hemorrhages, dilated and tortuous subcutaneous blood vessels, and defective vascular smooth muscle cell coverage. Mesangial cells in kidney glomeruli were also significantly reduced in GPR4-null neonates. Some neonates exhibited respiratory distress with airway lining cell metaplasia. To examine whether GPR4 is functionally involved in vascular pH sensing, an ex vivo aortic ring assay was used under defined pH conditions. Compared to wild-type aortas, microvessel outgrowth from GPR4-null aortas was less inhibited by acidic extracellular pH. Treatment with an analog of cAMP, a downstream effector of GPR4, abolished microvessel outgrowth bypassing the GPR4-knockout phenotype. These results suggest that GPR4 deficiency leads to partially penetrant vascular abnormalities during development and that this receptor functions in blood vessel pH sensing.

Published ahead of print on 4 December 2006.

Supplemental material for this article may be found at http://mcb.asm.org/.

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