Human trophoblast survival at low oxygen concentrations requires metalloproteinase-mediated shedding of heparin-binding EGF-like growth factor.
Heparin-binding EGF-like growth factor (HBEGF), which is expressed in the placenta during normal pregnancy, is down regulated 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 O(2) ( approximately 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% O(2) 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% O(2), 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 O(2) 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 O(2) 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.
Armant
D Randall
DR
Department of Anatomy and Cell Biology, C. S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, MI, USA. d.armant@wayne.edu
Kilburn
Brian A
BA
Petkova
Anelia
A
Edwin
Samuel S
SS
Duniec-Dmuchowski
Zophia M
ZM
Edwards
Holly J
HJ
Romero
Roberto
R
Leach
Richard E
RE
D017209:Apoptosis / Q000502:physiology*; D066259:Betacellulin; D002460:Cell Line; D002470:Cell Survival; D004151:Dipeptides / Q000494:pharmacology; D015536:Down-Regulation; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066260:Epiregulin; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D045726:Metalloproteases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010100:Oxygen / Q000502:physiology*; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D017434:Protein Structure, Tertiary; D066247:Receptor, ErbB-4; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014327:Trophoblasts / Q000502:physiology*
C587851:BTC protein, human; D066259:Betacellulin; D004151:Dipeptides; C587880:EREG protein, human; D066260:Epiregulin; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D016212:Transforming Growth Factor beta; D004815:Epidermal Growth Factor; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4; D045726:Metalloproteases; D010100:Oxygen