Activation of thromboxane and prostacyclin receptors elicits opposing effects on vascular smooth muscle cell growth and mitogen-activated protein kinase signaling cascades.
Thromboxane A2 stimulation of smooth muscle cells contributes to the development of vascular lesions after percutaneous transluminal coronary angioplasty. In view of this, we examined the signaling pathways stimulated by a thromboxane receptor agonist, U-46619, in cultures of rat aortic smooth muscle cells. Treatment of rat aortic smooth muscle cells with U-46619 induced cellular hypertrophy ([14C]leucine incorporation) without stimulating mitogenesis ([3H]thymidine incorporation). Analysis of signaling pathways elicited by U-46619 revealed enhanced tyrosine phosphorylation and increased enzymatic activity of mitogen-activated protein (MAP) kinase (Erk2). U-46619 also activated signaling proteins upstream of p21-ras, inducing tyrosine phosphorylation on Shc and complex formation between Shc and growth factor receptor binding protein-2 (GRB2). Exposure of cells to a stable prostacyclin analogue, ciprostene calcium, attenuated U-46619-induced cellular hypertrophy and MAP kinase activity. Ciprostene treatment elevated cellular cAMP and inhibited U-46619-induced tyrosine phosphorylation on Shc and Shc/GRB2 complex formation. These results demonstrate that stimulation of thromboxane A2 and prostacyclin receptors have opposing effects on smooth muscle cell hypertrophy and the signaling pathways associated with this process. We conclude that inhibition of Shc/GRB2 complex formation and MAP kinase activity by ciprostene may contribute to its ability to limit restenosis injury.
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002455:Cell Division; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000494:pharmacology; D051380:GRB2 Adaptor Protein; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D051381:Rats; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin / Q000502:physiology*; D017482:Receptors, Thromboxane / Q000502:physiology*; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; C495950:Grb2 protein, rat; D011450:Prostaglandin Endoperoxides, Synthetic; D011506:Proteins; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D011464:Epoprostenol; D000242:Cyclic AMP; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C045329:ciprostene; D013936:Thymidine