Editors' ChoiceReproductive Biology

New connections: Pregnancy-specific signaling

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Sci. Signal.  10 Oct 2017:
Vol. 10, Issue 500, eaaq1408
DOI: 10.1126/scisignal.aaq1408

Three papers highlight the cross-talk that occurs between mother and fetus during pregnancy.

Signaling pathways in many maternal tissues are rewired during pregnancy to accommodate the growing fetus, and conversely, maternally generated signals affect fetal growth and development. Three papers highlight the cross-talk that occurs between mother and fetus during pregnancy.

Maternal fever during the first trimester is an environmental trigger associated with commonly occurring cardiac and craniofacial birth defects that are not caused by specific mutations. Using chick or zebrafish embryos, Hutson et al. found that hyperthermia activated temperature-sensitive TRPV1 and TRPV4 ion channels in neural crest cells, which give rise to the tissues affected by the birth defects. Transiently activating either of these channels in neural crest cells in chick embryos resulted in cardiac and craniofacial birth defects similar to those induced by fever. These results suggest that TRPV1 or TRPV4 inhibition during first-trimester febrile episodes may reduce the incidence of common forms of birth defects.

The maternal immune system must develop tolerance toward the fetus during the first trimester, and recurrent miscarriages can be caused by a breakdown in this system. Li et al. found that the surface amounts of the receptor Tim-3 were increased on circulating natural killer (NK) cells in the first trimester of pregnancy. In contrast to NK cells from women with normal pregnancies, those from patients with recurrent miscarriage had decreased Tim-3 amounts and were defective in immune suppression. Abortion-prone mice were protected from fetal loss if given Tim-3-positive peripheral NK cells but not if given peripheral NK cells lacking Tim-3, suggesting that Tim-3+ peripheral NK cells promote maternal-fetal immune tolerance and may be a biomarker for recurrent miscarriage.

Preeclampsia is the onset of high blood pressure and proteinuria that acutely develops after about 20 weeks of pregnancy, which impairs fetal growth and can result in maternal organ damage. There are few treatment options available. Oxidative stress mediated by reactive oxygen species (ROS) has been proposed to increase the risk of preeclampsia by blocking blood vessel formation (angiogenesis) in the placenta. However, using a mouse model of preeclampsia, Nezu et al. found that decreasing ROS concentrations led to reduced placental angiogenesis, fetal growth, and maternal survival. In contrast, increased ROS concentrations resulted in greater placental angiogenesis and improved fetal and maternal outcomes. These results help to explain why antioxidants have been ineffective at preventing preeclampsia in clinical trials.

Together, these papers show how understanding the signaling pathways that become activated during pregnancy could lead to new treatments to prevent birth defects, recurrent miscarriages, or preeclampsia.

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