DIFFERENTIAL INDUCTION OF CYCLOOXYGENASE-2 IN HUMAN ARTERIAL AND VENOUS SMOOTH-MUSCLE - ROLE OF ENDOGENOUS PROSTANOIDS

Two isoforms of cyclooxygenase (COX) have been identified: a constitut ive isoform (COX-1), found in abundance in platelets and the vascular endothelium, and an ''inflammatory'' cytokine-inducible isoform (COX-2 ). Because COX metabolites regulate vascular smooth muscle cell (SMC) function and the interaction between the vessel and circulating compon ents, we have investigated the possibility that COX-2 can be induced i n human arterial or venous SMC. Untreated venous or arterial cells con tained undetectable levels of COX-1 or COX-2 and released low levels o f metabolites. After stimulation with interleukin-1 beta, tumor necros is factor-alpha, interferon-gamma, and bacterial lipopolysaccharide, b oth venous and arterial SMC expressed COX-2 protein and released incre ased amounts of prostaglandins. In addition, the induced release of PG E(2) was inhibited by the COX-2-selective inhibitor, L-745,337. When c ells were treated with the mixture of cytokines, venous SMC expressed greater amounts of COX-2 protein and released more prostaglandins than arterial SMC. Furthermore, when COX-2 activity was blocked by L-745,3 37, COX-2 expression in arterial SMC, but not in venous SMC, increased . Thus, this article describes, for the first time, that COX-2 is expr essed in greater amounts in venous SMC than in arterial SMC. Moreover, we show that this ''differential induction'' is due to a negative-fee dback pathway for COX-2 expression in arterial SMC but not in venous S MC. The ability of COX-2 activity to limit COX-2 expression in some ce lls but not others may contribute to the highly developed mechanisms i nvolved in prostanoid release.