title: Fluid Shear Stress Reduces 11ss-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 11ss-hydroxysteroid dehydrogenases (11ss-HSDs), thus determining body fluid volume and vascular responses. The impact of ss on 11ss-HSD2 activity was studied in the human JEG-3 cell line, a model for trophoblasts. JEG-3 cells do not express 11ss-HSD1; however, 11ss-HSD2 message and activity are measured via cortisol/cortisone conversion in cell lysates, and both are reduced by ss. The reduction in 11ss-HSD2 activity via ss is dose dependent and completely reversible after the discontinuation of ss. cAMP-dependent protein kinase A activation increased the 11ss-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 11ss-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 11ss-HSD2 activity. The 11ss-HSD2 activity was only partially restored by the tyrosine kinase inhibitor genistein; however, herbimycin A almost completely abolished the ss effect on 11ss-HSD2 activity. In conclusion, JEG-3 cells express 11ss-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.
authors.affiliation: Division of Nephrology/Hypertension, University of Berne, Berne, Switzerland.
authors.forename: C.-Bettina
authors.initials: CB
authors.lastname: Lanz
authors.forename: Maja
authors.initials: M
authors.lastname: Causevic
authors.forename: Christian
authors.initials: C
authors.lastname: Heiniger
authors.forename: Felix J.
authors.initials: FJ
authors.lastname: Frey
authors.forename: Brigitte M.
authors.initials: BM
authors.lastname: Frey
authors.forename: Markus G.
authors.initials: MG
authors.lastname: Mohaupt