Endothelin-1 stimulates human trophoblast cell migration through Cdc42 activation.

PURPOSE

This study investigated the role and mechanism of Cdc42 in Endothelin-1 (ET-1)-induced trophoblast cell migration.

METHODS

We examined ET-1-mediated stimulation of trophoblast migration with HTR-8/SVneo cells. Cdc42 activation was measured after ET-1 treatment of HTR-8/SVneo cells. To determine the ET receptor subtype involved in ET-1-mediated Cdc42 activation, experiments were performed in the presence of ET(A) and ET(B) receptor antagonists. Finally, using siRNA we knocked down the expression of Cdc42 to examine the involvement of Cdc42 in the regulation of ET-1-stimulated trophoblast cell migration.

RESULTS

ET-1 was shown to have a dose-dependent effect on trophoblast migration. At low concentrations of ET-1 (0.1 nmol/L) ET-1 had a stimulatory effect on cell migration. ET-1 (10 nmol/L) increased HTR-8/svneo cell migration index by 2.5 fold. ET-1 (10 nmol/L) elevated protein level and activity of Cdc42. ET-1 induced activation of Cdc42 GTPase was mediated by both ET(A) and ET(B). ET-1-induced cell migration was shown to be inhibited by Cdc42 siRNA.The inhibition was not mitigated by the addition of ET-1, suggesting that Cdc42 plays an important role in trophoblast migration and is obligatory for ET-1 action.

CONCLUSIONS

ET-1 stimulates EVT migration through Cdc42 activation.