Fluid Shear Stress Induces Lipocalin-Type Prostaglandin D 2 Synthase Expression in Vascular Endothelial Cells

Abstract

Abstract —Ligands for peroxisome proliferator–activated receptor γ, such as the thiazolidinedione class of antidiabetic drugs and 15-deoxy-Δ 12,14 -prostaglandin J 2 (15d-PGJ 2 ), modulate various processes in atherogenesis. In search of cells that generate prostaglandin D 2 (PGD 2 ), the metabolic precursor of 15d-PGJ 2 , we identified PGD 2 from culture medium of endothelial cells. To study how PGD 2 production is regulated in endothelial cells, we investigated the role of fluid shear stress in the metabolism of PGD 2 . Endothelial cells expressed the mRNA for the lipocalin-type PGD 2 synthase (L-PGDS) both in vitro and in vivo. Loading laminar shear stress using a parallel-plate flow chamber markedly enhanced the gene expression of L-PGDS, with the maximal effect being obtained at 15 to 30 dyne/cm 2 . The expression began to increase within 6 hours after loading shear stress and reached the maximal level at 18 to 24 hours. In contrast, shear stress did not alter the expression levels of PGI 2 synthase and thromboxane A 2 synthase. In parallel with the increase in the expression level of L-PGDS, endothelial cells released PGD 2 and 15d-PGJ 2 into culture medium. These results demonstrate that shear stress promotes PGD 2 production by stimulating L-PGDS expression and suggest the possibility that a peroxisome proliferator–activated receptor γ ligand is produced in vascular wall in response to blood flow.