Of mice and women: how Notch signaling ensures a healthy pregnancy

Nathan M. Hunkapiller and Susan J. Fisher

To accompany our research article in issue 138 (14) of Development, “A role for Notch signaling in trophoblast endovascular invasion and in the pathogenesis of pre-eclampsia,” we have been asked by the Node to provide a broader context to the work and to explore the possible medical implications of our findings.   http://dev.biologists.org/lookup/doi/10.1242/dev.066589

This work stems from our group’s interest in identifying the molecular and physiological mechanisms that govern placental function in normal human pregnancy and in pregnancy complications. Through their aggressive invasion of the uterine wall and resident blood vessels, human cytotrophoblasts (CTBs) anchor the placenta to the uterus and redirect maternal blood to the developing fetus. Interestingly, CTBs exhibit an arterial tropism, which suggests that these cells have the machinery to specifically recognize these vessels or are programmed to invade with an arterial bias. A study by a previous graduate student in our lab (Red-Horse et al., 2005) showed that CTBs achieve this specificity, in part, by co-opting mechanisms involved in neuronal guidance and vascular patterning. Specifically, as CTBs differentiate and invade the uterine wall, they upregulate expression of EphrinB2, which promotes their migration away from the placenta and toward maternal arteries in the uterine wall. As this molecular system is also utilized in developing vascular beds to segregate arteries and veins, we theorized that CTB invasion might be programmed by other upstream factors that govern vascular patterning, namely the Notch signaling family.

To test this hypothesis, we first used an immunolocalization approach to profile CTB expression of Notch family members in tissue sections of the human maternal-fetal interface. The results revealed extensive modulation of both receptors and ligands as the cells differentiated and invaded the uterine wall and resident arterioles. Functional blockade of Notch signaling reduced CTB invasion and expression of the arterial vascular marker, EphrinB2, which is normally upregulated as the cells invade maternal vessels. Second, we used a mouse model to further explore Notch function in this context. Employing a transgenic Notch reporter strain, we confirmed that Notch activity was highest in artery-associated trophoblasts. Deletion of the only receptor upregulated during trophoblast invasion (Notch2) highlighted the central importance of this signaling pathway in coordinating increases in utero-placental blood flow during pregnancy; trophoblast invasion of maternal arterioles failed, the blood canals that supply the placenta were smaller, and placental perfusion was decreased. The end result was litter-wide lethality proportional to the number of mutant offspring. Lastly, we asked whether defects in CTB expression of Notch family members were evident in preeclampsia, a pregnancy complication that is causally related to failed vascular transformation. An absence of endovascular CTB expression of the Notch ligand, JAG1, was frequently observed, suggesting that failures in Notch signaling are an important part of the pathogenesis of this condition.

Although development of the human placenta has many different components, we know that the tumor-like process in which CTBs invade the uterine vessels, which incorporates this transient organ into the uterine circulation, is a particularly key step. Why? Failures in this process lead to the dangerous pregnancy complication, pre-eclampsia (maternal high blood pressure, proteinuria and edema; impaired fetal growth). Our results suggest a molecular basis for abnormal placentation in this pregnancy complication and give us new clues about the pathways that are involved. These findings add weight to the theory that pre-eclampsia is associated with a failure of the mechanisms, borrowed from the vasculature, that integrate placental trophoblasts with uterine blood vessels.

Hunkapiller, N., Gasperowicz, M., Kapidzic, M., Plaks, V., Maltepe, E., Kitajewski, J., Cross, J., & Fisher, S. (2011). A role for Notch signaling in trophoblast endovascular invasion and in the pathogenesis of pre-eclampsia Development, 138 (14), 2987-2998 DOI: 10.1242/dev.066589

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