Thromboxane A2 and vascular smooth muscle cell proliferation

In the present study we describe the intracellular pathways for the transmission of growth signals by the potent vasoconstricting eicosanoids prostaglandin H2 and thromboxane A2 in smooth muscle cells from rat aorta. Carbocyclic thromboxane A2 and U46619 are stable thromboxane A2 mimetics acting at the common thromboxane A2/prostaglandin H2 receptor. Carbocyclic thromboxane A2 (10(-6) mol/L) induced an approximately 2.5-fold increase in [Ca2+]i above the basal value at 25 seconds. Maximal stimulation of the 42-kD mitogen-activated protein kinase isoform by both thromboxane A2 mimetics occurred at 5 minutes. Both thromboxane A2 mimetics at a concentration of 10(-6) mol/L induced the expression of c-fos and early growth response gene-1 (egr-1) mRNA, with a maximum at 30 minutes. Carbocyclic thromboxane A2 (10(-6) mol/L) induced a 3.3-fold increase in [3H]thymidine incorporation into cell DNA above the basal value and produced a 3.5-fold elevation of platelet-derived growth factor-BB-dependent [3H]thymidine incorporation into cell DNA. Similar effects of U46619 (10(-6) to 10(-5) mol/L) alone did in combination with platelet-derived growth factor-BB on cell DNA synthesis were obtained. The thromboxane A2/prostaglandin H2 receptor antagonist SQ29548 (10(-6) mol/L) completely suppressed the mitogenic effect of both thromboxane A2 mimetics (10(-6) mol/L). Pertussis toxin (10 to 100 ng/mL) did not influence the mitogenic effects of the thromboxane A2 mimetics. Carbocyclic thromboxane A2 (10(-6) mol/L) and platelet-derived growth factor-BB (20 ng/mL) per ser caused a 44% and 100% increase in cell number, respectively. In the presence of carbocyclic thromboxane A2 (10(-6) mol/L), platelet-derived growth factor-BB induced a 152% increase in cell number. Similar results were obtained with U46619 alone or in combination with platelet-derived growth factor-BB.