No abstract

Aldo deficiency due to a compromised MO step of Aldo synthesis favors extracellular volume depletion, and may account for an increased risk of placental hypoperfusion and consecutive development of preeclampsia. The sole presence of mutation V386A in preeclamptic mothers may identify a subgroup with an increased risk to develop preeclampsia during pregnancy.

Ang II decreases the activity of 11beta-HSD2 by an AT2 receptor- and MAPK-dependent mechanism. The decreased activity of 11beta-HSD2 increases the intracellular availability of cortisol, which might be relevant for the pathogenesis of hypertension and preeclampsia.

High aldosterone availability is associated with lower maternal blood pressure. In line with this observation, gain-of-function variants of the CYP11B2 reduce the risk of developing pre-eclampsia. Mutants of the mineralocorticoid receptor cannot explain the frequent syndrome of pre-eclampsia.

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 11␤-hydroxysteroid dehydrogenases (11␤-HSDs), thus determining body fluid volume and vascular responses. The impact of ss on 11␤-HSD2 activity was studied in the human JEG-3 cell line, a model for trophoblasts. JEG-3 cells do not express 11␤-HSD1; however, 11␤-HSD2 message and activity are measured via cortisol/cortisone conversion in cell lysates, and both are reduced by ss. The reduction in 11␤-HSD2 activity via ss is dose dependent and completely reversible after the discontinuation of ss. cAMP-dependent protein kinase A activation increased the 11␤-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 11␤-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 11␤-HSD2 activity. The 11␤-HSD2 activity was only partially restored by the tyrosine kinase inhibitor genistein; however, herbimycin A almost completely abolished the ss effect on 11␤-HSD2 activity. In conclusion, JEG-3 cells express 11␤-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. (Hypertension. 2001;37:160-169.)