Thromboxane A 2 and Vascular Smooth Muscle Cell Proliferation

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Abstract
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 [Ca 2+ ] 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 [ 3 H]thymidine incorporation into cell DNA above the basal value and produced a 3.5-fold elevation of platelet-derived growth factor-BB–dependent [ 3 H]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.