Up-regulation of endothelial cyclooxygenase-2 and prostanoid synthesis by platelets - Role of thromboxane A(2)

Platelet-vascular endothelial cell interactions are central to the maintena nce of vascular homeostasis. Thromboxane A(2) (TXA(2)) and prostacyclin (pr ostaglandin (PG) I-2) are the major products of cyclooxygenase (COX) metabo lism by platelets and the vascular endothelium, respectively. Here we repor t the effects of platelet-endothelial interactions on human umbilical vein endothelial cells (HUVECs) COX-2 expression and prostanoid synthesis. Co-in cubation of platelets with HUVECs resulted in a dose-dependent induction in COX-2 expression. This was accompanied by a relatively small increase in t hromboxane B-2 synthesis (2 ng) by comparison to the production of 6-keto-P GF(1 alpha) and PGE(2), which increased by similar to 14 and 12 ng, respect ively. Abrogation of platelet-HUVEC interactions excluded direct cell-cell contact as a required event. Preincubation of HUVECs with SQ29548, a TXA(2) receptor antagonist, dose-dependently inhibited platelet-induced COX-2 exp ression and prostanoid synthesis. Similarly, if platelet TXA(2) synthesis w as inhibited no induction of COX-2 was observed. Furthermore, a TXA(2) anal og, carbocyclic TXA(2), induced HUVEC COX-2 expression and the synthesis of 6-keto-PGF(1 alpha). and PGE2. This was also associated with an increase i n the expression and activity of PGI synthase and PGE synthase but not TX s ynthase. Platelet co-incubation (or TXA(2)) also selectively activated the p44/42 mitogen-activated protein kinase pathway to regulate HUVEC COX-2 exp ression. Thus it seems that platelet-derived TXA(2) can act in a paracrine manner to up-regulate endothelial COX-2 expression and PGI(2) synthesis. Th ese observations are of particular importance given the recent observations regarding selective COX-2 inhibitors and the suppression of PGI(2) synthes is.