Serotonin Stimulates the Expression of Thrombin Receptors in Cultured Vascular Smooth Muscle Cells

BACKGROUND: Thrombin has been implicated in the development of intimal thickening after balloon angioplasty. The action of thrombin on vascular cells involves the proteolytic activation of G protein-coupled receptors that are subjected to rapid and irreversible homologous desensitization. Hence, the amount and availability of thrombin-activatable receptors play a determinant role in thrombin responsiveness. The possibility that the platelet-derived product serotonin (5-HT) regulates expression of the thrombin receptor was examined in cultured rat aortic vascular smooth muscle cells. METHODS AND RESULTS: Thrombin receptor expression was assessed at the mRNA level by Northern blot analysis and functionally by measurement of the release of 6-ketoprostaglandin F1 alpha. 5-HT significantly enhanced thrombin receptor mRNA levels in a time- and concentration-dependent manner, an effect that was abolished by 5-HT2 receptor antagonists and by inhibition of protein kinase C but only slightly affected by inhibitors of protein tyrosine kinases. Enhanced thrombin receptor mRNA levels after exposure to 5-HT were associated with an increase in the thrombin-induced release of 6-ketoprostaglandin F1 alpha. CONCLUSIONS: 5-HT stimulates the expression of thrombin receptors in vascular smooth muscle cells, probably via activation of 5-HT2 receptors and the subsequent activation of protein kinase C and possibly also protein tyrosine kinases. The upregulation of the synthesis of plasma membrane thrombin receptors by 5-HT released from aggregating platelets at sites of vascular injury may potentiate the mitogenic and constrictor actions of thrombin in the vascular wall.