Fluid shear stress reduces 11 beta-hydroxysteroid dehydrogenase type 2

In pregnancy, invading trophoblasts represent the inner vascular border of maternal spiral arteries and are exposed to elevated shear stress (ss) in h ypertensive disorders. Intracellular cortisol availability is regulated by 11 beta -hydroxysteroid dehydrogenases (11 beta -HSDs), thus determining bo dy fluid volume and vascular responses. The impact of ss on 11 beta -HSD2 a ctivity was studied in the human JEG-3 cell line, a model for trophoblasts. JEG-3 cells do not express 11 beta -HSD1; however, 11 beta -HSD2 message a nd activity are measured via cortisol/cortisone conversion in cell lysates, and both are reduced by ss. The reduction in 11 beta -HSD2 activity via ss is dose dependent and completely reversible after the discontinuation of s s. cAMP-dependent protein kinase A activation increased the 11 beta -HSD2 a ctivity yet did not prevent the ss response. The ss response was completely protein kinase C independent. The mitogen-activated protein kinase kinase inhibitor PD-098059 enhanced 11 beta -HSD2 activity in static conditions ye t only ameliorated the ss effect. Cytochalasin D disrupts focal adhesion (F A)-cytoskeleton interactions and abolished the ss-induced tyrosine phosphor ylation of FA kinase dose-dependently, thus maintaining 11 beta -HSD2 activ ity. The 11 beta -HSD2 activity was only partially restored by the tyrosine kinase inhibitor genistein; however, herbimycin A almost completely abolis hed the ss effect on 11 beta -HSD2 activity. In conclusion, JEG-3 cells exp ress 11 beta -HSD2, which is downregulated by ss. Regulatory mechanisms inv olve transcriptional control and require intact FA-cytoskeleton signaling a nd phosphorylation of FA kinase. Thus, ss adds to an enhanced intracellular availability of cortisol, which may ultimately support a vasoconstrictive vascular response.