Published online before print December 21, 2007

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Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.070640

Accepted for publication September 17, 2007.

Article

Severe Intrauterine Growth Restriction Pregnancies Have Increased Placental Endoglin Levels. Hypoxic Regulation via Transforming Growth Factor-3

Yoav Yinon^*, Ori Nevo^*, Jing Xu^*, Ariel Many^*, Alessandro Rolfo^*, Tullia Todros, Martin Post, and Isabella Caniggia^*@

From the Department of Obstetrics and Gynecology,* Mount Sinai Hospital, Samuel Lunenfeld Research Institute, the Department of Pediatrics, Hospital for Sick Children, and the Department of Physiology, University of Toronto, Toronto, Canada; and the Department of Obstetrics and Gynecology, University of Turin, Turin, Italy

^@ To whom correspondence should be addressed. E-mail: caniggia{at}mshri.on.ca.

	Abstract

Endoglin, a co-receptor for transforming growth factor (TGF)-₁ and -₃ is expressed in the human placenta and plays an important role in the pathogenesis of preeclampsia. Because preeclampsia is associated with hypoxia, and because TGF-3 is overexpressed in preeclamptic pregnancies, we examined the effect of oxygen and TGF-3 on placental endoglin expression and investigated its expression in pathological models of placental hypoxia such as intrauterine growth restriction (IUGR) pregnancies. Endoglin expression was high at 4 to 9 weeks of gestation, when oxygen tension is low, and decreased after 10 weeks, when oxygen tension increases. Exposure of villous explants to low oxygen (3% O₂) resulted in elevated expression of both membrane and soluble endoglin compared to standard conditions (20% O₂). Moreover, addition of TGF-₃ to villous explants under low oxygen conditions increased the expression of endoglin compared to nontreated explants whereas addition of TGF-₃-neutralizing antibodies inhibited the low oxygen stimulatory effect on endoglin expression. Endoglin and soluble endoglin expression were significantly increased in placentas of IUGR singletons compared to controls and in the IUGR twin placentas relative to both the control co-twin and the normal twins. These data demonstrate that oxygen regulates the placental expression of endoglin via TGF-₃. Reduced placental perfusion leading to placental hypoxia might contribute to the increased expression of endoglin in IUGR pregnancies.