Human trophoblast survival at low oxygen concentrations requires metalloproteinase-mediated shedding of heparin-binding EGF-like growth factor

Abstract

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 O 2 (~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 metalloproteinasemediated 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.

Prevention of gravidic endothelial hypertension by aspirin treatment administered from the 8th week of gestation

“…3 These hypertensive diseases are of placental origin, because the delivery is generally followed by the disappearance of symptoms, often in less than 1 week. 4 The link between placental dysfunction and the mother's syndrome has been quite elusive until the last 10 years or so, when the hypothesis of residual syncytiotrophoblastic material from placental shedding 5 or placenta microparticles 6 was put forward. This material can release vasoactive substances to the maternal blood flow, which in turn could durably affect the maternal endothelium throughout the body.…”

Diminished survival of human cytotrophoblast cells exposed to hypoxia/reoxygenation injury and associated reduction of heparin-binding epidermal growth factor-like growth factor

“…Heparin-binding EGF-like growth factor (HBEGF) is expressed in the placenta through out pregnancy (10,11) and is upregulated by low O 2 through a post-transcriptional mechanism to inhibit apoptosis (12). Signaling via HER1 or HER4, known HBEGF receptors, is required for both HBEGF upregulation and protection against apoptosis (12).…”

“…Heparin-binding EGF-like growth factor (HBEGF) is expressed in the placenta through out pregnancy (10,11) and is upregulated by low O 2 through a post-transcriptional mechanism to inhibit apoptosis (12). Signaling via HER1 or HER4, known HBEGF receptors, is required for both HBEGF upregulation and protection against apoptosis (12). Consistent with its proposed role as a prosurvival factor in response to ROS in first trimester cytotrophoblast, HBEGF expression is expressed robustly in trophoblast, but is reduced about five-fold in preeclamptic placentas (11).…”

The physiologic and therapeutic role of Heparin in implantation and placentation

“…Experimental evidence suggests that this environment is essential for both fetal and placental development, and premature exposure to normal oxygen concentrations is associated with increased rate of pregnancy complications such as preeclampsia, IUGR and miscarriage 35 . First trimester human cytotrophoblast cell survival at 2% O2 is dependent on HB-EGF signaling 36 . Indeed, HB-EGF expression is up regulated by hypoxia, and it functions as a mitogen and potent cell survivor factor during stress.…”

“…Subsequent transphosphorylation of HER cytoplasmatic domains at tyrosine residues initiates a downstream signaling that increases proHB-EGF accumulation and inhibits apoptosis. This positive feedback loop upregulates HBEGF secretion to achieve extracellular HB-EGF levels sufficient to maintain cell survival at 2% O2 36 . Thus, we propose that the accumulating evidence suggests that the beneficial effect of heparin in preventing placental mediated pregnancy complications may derive from its effect on HB-EGF expression and concentration, especially during the first trimester.…”