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Endothelin-1 Attenuates Apoptosis in Cultured Trophoblasts From Term Human Placentas

Departments of Obstetrics and Gynecology, Washington University School of Medicine, St Louis, Missouri, mila.cervarzivkovic{at}meduni-graz.at, University of Graz, Graz, Austria

C. Hu, PhD

Departments of Obstetrics and Gynecology, Washington University School of Medicine, St Louis, Missouri

A. Barton, MS

Departments of Obstetrics and Gynecology, Washington University School of Medicine, St Louis, Missouri

Y. Sadovsky, MD

Departments of Obstetrics and Gynecology, Washington University School of Medicine, St Louis, Missouri

G. Desoye, PhD

University of Graz, Graz, Austria

U. Lang, MD

University of Graz, Graz, Austria

D.M. Nelson, MD, PhD

Departments of Obstetrics and Gynecology, Washington University School of Medicine, St Louis, Missouri

The authors test the hypothesis that endothelin-1 (ET-1) modulates apoptosis in human term trophoblasts. Primary cultures of cytotrophoblasts from term human placentas (n = 5) were cultured for 16 hours total or 24 hours prior to harvest at 72 hours in atmospheres of <1%, 8%, and 20% oxygen, in the presence of 10% serum, ET-1 (1-100 pmol/mL), both, or neither. The apoptotic cleavage products of poly-ADP-ribose polymerase and cytokeratin 18 filaments were quantified by Western analysis and immunocytochemistry. The expression of BAD, pBAD-serine112, p53, and 2 isoforms of MDM2 were quantified by immunoblotting, and endothelin A and B receptors were analyzed by immunocytochemistry. Compared to vehicle control, increasing concentrations of ET-1 reduce by 3- to 6-fold the level of apoptosis in cytotrophoblasts exposed to serum-free conditions at 20% oxygen. Similarly, syncytiotrophoblast cultures grown for 24 hours without serum in 100 pmol/mL ET-1 show a 3-fold lower level of apoptosis compared with vehicle control. ET-1 significantly reduces apoptosis in cultures exposed to 20% oxygen but not in cultures exposed to 8% or 1% oxygen. The effect of ET-1 on apoptosis in 20% oxygen is accompanied by reduced p53 expression and is correlated with enhanced expression of endothelin B receptor, compared to cultures in 8% or 1% oxygen. ET-1 reduces apoptosis in cultured human trophoblasts, and this finding suggests a role for ET-1 in protecting trophoblasts against injury.

Key Words: Endothelin-1,apoptosis • trophoblast • placenta.

Reproductive Sciences, Vol. 14, No. 5, 430-439 (2007)
DOI: 10.1177/1933719107305801


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