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First published online 11 January 2006
doi: 10.1242/dev.02237

Development 133, 751-759 (2006)
Published by The Company of Biologists 2006
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Human trophoblast survival at low oxygen concentrations requires metalloproteinase-mediated shedding of heparin-binding EGF-like growth factor

D. Randall Armant1,2,*, Brian A. Kilburn2, Anelia Petkova2, Samuel S. Edwin3, Zophia M. Duniec-Dmuchowski2, Holly J. Edwards2, Roberto Romero3 and Richard E. Leach4

1 Department of Anatomy and Cell Biology, C. S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, MI, USA.
2 Department of Obstetrics and Gynecology, C. S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, MI, USA.
3 Perinatology Research Branch, National Institute of Child Health and Human Development, NIH, DHHS, Bethesda, MD, USA.
4 Departments of Obstetrics and Gynecology, and Physiology and Biophysics, University of Illinois School of Medicine, Chicago, IL, USA.

* Author for correspondence (e-mail: d.armant{at}wayne.edu)

Accepted 5 December 2005

Heparin-binding EGF-like growth factor (HBEGF), which is expressed in the placenta during normal pregnancy, is downregulated in pre-eclampsia, a human pregnancy disorder associated with poor trophoblast differentiation and survival. This growth factor protects against apoptosis during stress, suggesting a role in trophoblast survival in the relatively low O2 (~2%) environment of the first trimester conceptus. Using a well-characterized human first trimester cytotrophoblast cell line, we found that a 4-hour exposure to 2% O2 upregulates HBEGF synthesis and secretion independently of an increase in its mRNA. Five other expressed members of the EGF family are largely unaffected. At 2% O2, signaling via HER1 or HER4, known HBEGF receptors, is required for both HBEGF upregulation and protection against apoptosis. This positive-feedback loop is dependent on metalloproteinase-mediated cleavage and shedding of the HBEGF ectodomain. The restoration of trophoblast survival by the addition of soluble HBEGF in cultures exposed to low O2 and metalloproteinase inhibitor suggests that the effects of HBEGF are mediated by autocrine/paracrine, rather than juxtacrine, signaling. Our results provide evidence that a post-transcriptional mechanism induced in trophoblasts by low O2 rapidly amplifies HBEGF signaling to inhibit apoptosis. These findings have a high clinical significance, as the downregulation of HBEGF in pre-eclampsia is likely to be a contributing factor leading to the demise of trophoblasts.

Key words: Trophoblast, Placenta, Oxygen, HBEGF (HB-EGF), Metalloproteinases, Apoptosis, Human, Pregnancy


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