Upregulation of Prostacyclin Synthesis–Related Gene Expression by Shear Stress in Vascular Endothelial Cells

Abstract

Abstract-Prostacyclin (prostaglandin I 2 , PGI 2 ) has a variety of functions, including inhibition of smooth muscle cell proliferation, vasodilation, and antiplatelet aggregation. PGI 2 production in endothelial cells has been reported to increase biphasically after shear loading, but the underlying mechanism is not well understood. To clarify the mechanism for the second phase of PGI 2 upregulation, we examined the gene expression of the enzymes involved in PGI 2 production in human umbilical vein endothelial cells (HUVECs) after shear-stress (24 dyne/cm 2 ) loading. The production of 6-keto-PGF 1␣ , a stable metabolite of PGI 2 , increased time-dependently under shear stress. The arachidonic acid liberation from membrane phospholipids in HUVECs after 12 hours of shear loading was increased significantly compared with the static condition. No change was observed for cytosolic phospholipase A 2 expression, as detected by reverse transcription-polymerase chain reaction and Western blotting. Cyclooxygenase (COX)-1 mRNA increased after 1 hour of shear loading, and the increase lasted for 12 hours, the longest time tested, whereas COX-2 mRNA increased after 1 hour of shear loading and peaked at 6 hours. An increase of COX-1 expression was detected at 12 hours of shear loading by Western blotting. No expression of COX-2 was detected in the static control, but induced expression was observed at 6 hours after shear loading. PGI 2 synthase was also found to be upregulated. These results suggest that the elevated PGI 2 production by shear stress is mediated by increased arachidonic acid release and a combination of increased expression of COXs and PGI 2 synthase. (Arterioscler Thromb Vasc Biol. 1998;18:1922-1926 Key Words: shear stress Ⅲ prostacyclin Ⅲ gene regulation Ⅲ endothelial cells V ascular endothelial cells were once considered to be a passive, antithrombogenic barrier; however, they are now known to have a variety of functions, such as regulation of vascular tone, atherogenic progression, and smooth muscle cell proliferation. Endothelial functions are regulated not only by humoral factors, such as growth factors and cytokines, but also by mechanical forces, such as shear stress, pressure, and stretch. Shear stress in particular plays an important role in endothelial functions. Shear stress can mediate a change in morphology and the release of various vasoactive substances from endothelial cells.1,2 Decreased shear stress has been suggested to be involved in the pathogenesis of atherosclerosis. It has been reported that areas of low shear stress are more likely to become sites of atherosclerosis 3 and that low shear stress promotes the formation of intimal hyperplasia. 4 Previous studies have shown that the release of NO, C-type natriuretic peptide, and prostaglandin I 2 (PGI 2 ) is augmented by shear stress through elevated intracellular Ca 2ϩ and increased transcription of endothelial NO synthase mRNA and C-type natriuretic peptide mRNA. [5][6][7] Frangos et al 7 reported that shear stress increases PGI 2 prod...

Reactive oxygen species modulate coronary wall shear stress and endothelial function during hyperglycemia

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Roles of Cyclooxygenase (COX)-1 and COX-2 in Prostanoid Production by Human Endothelial Cells: Selective Up-Regulation of Prostacyclin Synthesis by COX-2

“…However, the endothelium has been reported to synthesize TXA 2 in addition to PGI 2 (6), and both COX isoforms have been observed, with only COX-1 being detectable in unstimulated cells (6,7). Endothelial COX-2 can be up-regulated in vitro by inflammatory stimuli (6,8) and shear stress (7,9). Because the balance between PGI 2 and TXA 2 production is central in the maintenance of vascular tone and platelet aggregation, determination of the roles of endothelial COX isozymes, particularly with regard to the contribution of COX-2 in the regulation of prostanoid biosynthesis by the endothelium, is important.…”

The impact of baseline artery diameter on flow-mediated vasodilation: a comparison of brachial and radial artery responses to matched levels of shear stress

“…In healthy arteries, increases in blood flow-associated shear stress lead to the release of vasodilators [e.g., nitric oxide (NO), endothelial-derived hyperpolarizing factor (EDHF), and prostacyclin] by the endothelium, resulting in an endotheliumdependent vasodilation [flow-mediated vasodilation (FMD)] (1,3,28,35). An inverse relationship between baseline vessel diameter and the magnitude of the conduit artery FMD response in the arm has been reported by several studies (19,42,49,52).…”