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Inflammatory stress increases receptor for lysophosphatidylcholine in human microvascular endothelial cells

Departments of ¹Pharmacology and ²Medicine, Rush-Presbyterian St. Luke's Medical Center; Departments of ³Medicine and ⁴Surgery, Cook County Hospital, Chicago Illinois, 60612; and ⁵Department of Pediatrics, The Johns Hopkins University, Baltimore, Maryland 21205

Submitted 21 April 2003 ; accepted in final form 11 June 2003

ABSTRACT

The atherogenic serum lysophosphatidylcholine (LPC) is known to mediate vascular endothelial responses ranging from upregulation of adhesion molecules and growth factors to secretion of chemokines and superoxide anion. We investigated whether endothelial cells express receptors for LPC, which may account for their actions. Human brain microvascular (HBMEC) and dermal microvascular endothelial cells (HMEC) were prepared for RT-PCR analysis for possible expression of the G protein-coupled receptors, GPR4 and G2A, which are believed to be specific LPC receptors. Results indicated that HBMEC expressed low basal GPR4 mRNA, but stimulation with tumor necrosis factor- (TNF-) (100 U/ml) or H₂O₂ (50 µmol/l) for 2 h or overnight upregulated expression severalfold. In contrast, HMEC expressed high basal GPR4 mRNA, which was not further increased by either TNF- or H₂O₂ stimulation. Another LPC receptor, G2A, was not detected in either endothelial cell type. Competition binding studies were made to evaluate specific binding of [³H]LPC to the intact endothelial cell monolayer. Basal specific [³H]LPC binding in HBMEC was approximately eight times lower than in HMEC; however, TNF- or H₂O₂ stimulation increased [³H]LPC binding on HMBEC but not HMEC. The results indicated that GPR4 expression was consistent with specific [³H]LPC binding. Overall, we report that endothelial cells selectively expressed GPR4, a specific LPC receptor. Furthermore, GPR4 expression by HBMEC, but not HMEC, was increased by inflammatory stresses. We conclude that endogenous GPR4 in endothelial cells may be a potential G protein-coupled receptor by which LPC signals proinflammatory activities.

G protein-coupled receptors 4 and 2A; oxidants; tumor necrosis factor-; specific binding

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