ACTIVATION OF THROMBOXANE AND PROSTACYCLIN RECEPTORS ELICITS OPPOSINGEFFECTS ON VASCULAR SMOOTH-MUSCLE CELL-GROWTH AND MITOGEN-ACTIVATED PROTEIN-KINASE SIGNALING CASCADES

Thromboxane A(2) stimulation of smooth muscle cells contributes to the development of vascular lesions after percutaneous transluminal coron ary angioplasty. In view of this, we examined the signaling pathways s timulated by a thromboxane receptor agonist, U-46619, in cultures of r at aortic smooth muscle cells. Treatment of rat aortic smooth muscle c ells with U-46619 induced cellular hypertrophy ([C-14]leucine incorpor ation) without stimulating mitogenesis ([H-3]thymidine incorporation). Analysis of signaling pathways elicited by U-46619 revealed enhanced tyrosine phosphorylation and increased enzymatic activity of mitogen-a ctivated protein (MAP) kinase (Erk2). U-46619 also activated signaling proteins upstream of p21-ras, inducing tyrosine phosphorylation on Sh e 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 a nd inhibited U-46619-induced tyrosine phosphorylation on She and Shc/G RB2 complex formation. These results demonstrate that stimulation of t hromboxane A(2) and prostacyclin receptors have opposing effects on sm ooth muscle cell hypertrophy and the signaling pathways associated wit h this process. We conclude that inhibition of Shc/GRB2 complex format ion and MAP kinase activity by ciprostene may contribute to its abilit y to limit restenosis injury.