THROMBOXANE A(2) 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 H-2 and thromboxane A(2) in smooth muscle cells from rat aorta. Carbocyclic thromboxane A(2) and U46619 are stable thromboxane A(2) mimetics acting at the common thromboxane A(2)/prostaglandin H-2 receptor. Carbocyclic thromboxane A(2) (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 A(2) mimetics occurred at 5 minutes. Both thromboxane A(2) 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 A(2) (10(-6) mol/L) induced a 3.3-fold increase in [H-3]thymidine incorporation into cell DNA above the basal value and produced a 3.5-fold elevation of platelet-derived growth factor-BB-dependent [H-3]thymidine incorporation into cell DNA. Similar effects of U46619 (10(-6) to 10(-5) mol/L) alone and in combination with platelet-derived growth factor-BB on cell DNA synthesis were obtained. The thromboxane A(2)/prostaglandin H-2 receptor antagonist SQ29548 (10(-6) mol/L) completely suppressed the mitogenic effect of both thromboxane A(2) mimetics (10(-6) mol/L). Pertussis toxin (10 to 100 ng/mL) did not influence the mitogenic effects of the thromboxane A(2) mimetics. Carbocyclic thromboxane A(2) (10(-6) mol/L) and platelet-derived growth factor-BB (20 ng/mL) per se caused a 44% and 100% increase in cell number, respectively. In the presence of carbocyclic thromboxane A(2) (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.