Testosterone treatment increases thromboxane function in rat cerebral arteries

We previously showed that testosterone, administered in vivo, increases the tone of cerebral arteries. A possible underlying mechanism is increased vasoconstriction through the thromboxane A(2) (TxA(2)) pathway. Therefore, we investigated the effect of chronic testosterone treatment ( 4 wk) on TxA(2) synthase levels and the contribution of TxA(2) to vascular tone in rat middle cerebral arteries (MCAs). Using immunofluorescence and confocal microscopy, we demonstrated that TxA(2) synthase is present in MCA segments in both smooth muscle and endothelial layers. Using Western blot analysis, we found that TxA(2) synthase protein levels are higher in cerebral vessel homogenates from testosterone-treated orchiectomized (ORX + T) rats compared with orchiectomized ( ORX) control animals. Functional consequences of changes in cerebrovascular TxA(2) synthase were determined using cannulated, pressurized MCA segments in vitro. Constrictor responses to the TxA(2) mimetic U-46619 were not different between the ORX + T and ORX groups. However, dilator responses to either the selective TxA2 synthase inhibitor furegrelate or the TxA(2)-endoperoxide receptor (TP) antagonist SQ-29548 were greater in the ORX + T compared with ORX group. In endothelium-denuded arteries, the dilation to furegrelate was attenuated in both the ORX and ORX + T groups, and the difference between the groups was abolished. These data suggest that chronic testosterone treatment enhances TxA(2)-mediated tone in rat cerebral arteries by increasing endothelial TxA(2) synthesis without altering the TP receptors mediating constriction. The effect of in vivo testosterone on cerebrovascular TxA(2) synthase, observed here after chronic hormone administration, may contribute to the risk of vasospasm and thrombosis related to cerebrovascular disease.