Carine Gennari-Moser, Eliyahu V. Khankin, Simone Schüller, Geneviève Escher, Brigitte M. Frey, C.-Bettina Portmann, Marc U. Baumann, Andrea D. Lehmann, Daniel Surbek, S. Ananth Karumanchi, Felix J. Frey, and Markus G. Mohaupt*
Departments of Nephrology/Hypertension (C.G.-M., S.S., G.E., B.M.F., F.J.F., M.G.M.) and Obstetrics and Gynecology (C.-B.P., M.U.B., D.S.), University Hospital Bern, Inselspital, 3010 Berne, Switzerland; Division of Vascular and Molecular Medicine (E.V.K., S.A.K.), Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215; and Division of Histology (A.D.L.), Institute of Anatomy, University of Bern, 3000 Berne, Switzerland
* To whom correspondence should be addressed. E-mail: firstname.lastname@example.org.
During pregnancy, trophoblasts grow to adapt the feto-maternal unit to fetal requirements. Aldosterone and cortisol levels increase, the latter being inactivated by a healthy placenta. By contrast, preeclamptic placental growth is reduced while aldosterone levels are low and placental cortisol tissue levels are high due to improper deactivation. Aldosterone acts as a growth factor in many tissues, whereas cortisol inhibits growth.
We hypothesized that in preeclampsia low aldosterone and enhanced cortisol availability might mutually affect placental growth and function. Proliferation of cultured human trophoblasts was time- and dose-dependently increased with aldosterone (P < 0.04 to P < 0.0001) and inhibited by spironolactone and glucocorticoids (P < 0.01). Mineralo- and glucocorticoid receptor expression and activation upon agonist stimulation was verified by visualization of nuclear translocation of the receptors.
Functional aldosterone deficiency simulated in pregnant mice by spironolactone treatment (15 ?g/g body weight/day) led to a reduced fetal umbilical blood flow (P < 0.05). In rat (P < 0.05; R2 = 0.2055) and human (X2 = 3.85; P = 0.0249) pregnancy, placental size was positively related to plasma aldosterone.
Autocrine production of these steroid hormones was excluded functionally and via the absence of specific enzymatic transcripts for CYP11B2 and CYP11B1. In conclusion, activation of mineralocorticoid receptors by maternal aldosterone appears to be required for trophoblast growth and a normal feto-placental function.
Thus, low aldosterone levels and enhanced cortisol availability may be one explanation for the reduced placental size in preeclampsia and related disorders.