Fluid shear stress reduces 11β-hydroxysteroid dehydrogenase type 2

Abstract

In pregnancy, invading trophoblasts represent the inner vascular border of maternal spiral arteries and are exposed to elevated shear stress (ss) in hypertensive disorders. Intracellular cortisol availability is regulated by 11β-hydroxysteroid dehydrogenases (11β-HSDs), thus determining body fluid volume and vascular responses. The impact of ss on 11β-HSD2 activity was studied in the human JEG-3 cell line, a model for trophoblasts. JEG-3 cells do not express 11β-HSD 1; however, 11β-HSD2 message and activity are measured via cortisol/cortisone conversion in cell lysates, and both are reduced by ss. The reduction in 11β-HSD2 activity via ss is dose dependent and completely reversible after the discontinuation of ss. cAMP-dependent protein kinase A activation increased the 11β-HSD2 activity 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 11β-HSD2 activity in static conditions yet only ameliorated the ss effect. Cytochalasin D disrupts focal adhesion (FA)-cytoskeleton interactions and abolished the ss-induced tyrosine phosphorylation of FA kinase dose-dependently, thus maintaining 11β-HSD2 activity. The 11β-HSD2 activity was only partially restored by the tyrosine kinase inhibitor genistein; however, herbimycin A almost completely abolished the ss effect on 11β-HSD2 activity. In conclusion, JEG-3 cells express 11β-HSD2, which is downregulated by ss. Regulatory mechanisms involve transcriptional control and require intact FA-cytoskeleton signaling and phosphorylation of FA kinase. Thus, ss adds to an enhanced intracellular availability of cortisol, which may ultimately support a vasoconstrictive vascular response.