miRNA‐210: a hypoxamiRyad of possibilities

During early pregnancy, the uterine vasculature undergoes major adaptive responses to facilitate unimpeded blood flow to the placenta and thus promote the growth of the fetus. The physiological conversion of human uterine spiral arteries is associated with loss of elastic tissue and smooth muscle from the vessel wall, leading to funnel-shape dilatation, which ensures reduced vascular resistance and appropriate blood supply to the fetus (Burton et al. 2009). The conversion of spiral arteries is deficient in pathological diseases of pregnancy, such as in early onset pre-eclampsia and intrauterine growth restriction (IUGR). Under these circumstances, there is abnormal placental development, leading to retention of spiral artery reactivity, impaired placental blood flow with ischaemia and reperfusion, usually manifested as abnormal spiral and uterine artery Doppler indices, (Redman & Sargent, 2005; Burton et al. 2009). The mal-perfused placenta can trigger the secretion of a mixture of placental factors, including anti-angiogenic agents, pro-inflammatory cytokines and apoptotic debris, that culminates in an enhanced maternal inflammatory response, which in turn can induce systemic endothelial dysfunction and the maternal syndrome of pre-eclampsia (Cindrova-Davies, 2014). Placental oxidative stress leads to the regression of placental fetal capillaries and atherosis, remodelling and increased wall thickness of stem villous arteries, thereby impairing placental transfer, which promotes chronic fetal hypoxia and IUGR (Lu et al. 2017). There are over 140 million people living at high altitude, comprising the largest single group at risk of fetal growth restriction. Pregnancy at high altitude represents an experiment of nature characterised by the exposure of the fetoplacental unit to chronic hypobaric hypoxia. It is established that high altitude pregnancy reduces human birth weight ( 100 g per 1000 m of ascent), with an increased prevalence of IUGR (Soria et al. 2013) and pre-eclampsia (Keyes et al. 2003). However, the mechanisms involved are not fully understood, thereby preventing targets for human clinical intervention. Chronic hypoxia is considered a key mediator of the pathophysiology of IUGR in fetal development at high altitude. This is supported by evidence of a 40% reduction in the fetal growth in development at 3600 m above sea level (PO2 reduced 30%) and reversal of the high altitude-induced fetal growth restriction with oxygen supplementation in a chicken embryo model (Giussani et al. 2007). The chronic hypoxia of human pregnancy at high altitude can also affect the maternal adaptation to pregnancy, for example by impairing the increase in uterine artery blood flow with advancing gestation in human pregnancy (Julian et al. 2009). However, despite this and the lowering of ambient arterial partial pressure of oxygen, normal oxygen delivery to the fetus appears to be maintained at high altitude. The latter may partly be due to increased erythropoiesis in both the maternal and fetal circulations, and partly due to modifications at the level of the placenta (Postigo et al. 2009). It has been proposed that the placenta at high altitude undergoes metabolic remodelling, which spares oxygen delivery to the fetus at the expense of increased placental glucose consumption (Illsley et al. 2010). Indeed, exposure to chronic hypobaric hypoxia causes mild placental endoplasmic reticulum stress, which modulates protein synthesis and slows proliferation, thereby contributing to reduced placental volume and low birth weight (Yung et al. 2012). In addition, protein synthesis inhibition also suppresses mitochondrial electron transport chain function in hypoxic placentas, which is likely mediated by upregulation of microRNA-210 (miR-210) in high altitude placentas (Colleoni et al. 2013). An increased vascular resistance and consequent reduction in blood flow in the uteroplacental circulation thus seems to be the leading cause of IUGR in high altitude pregnancies. Similarly, increased uterine vascular resistance due to deficient spiral artery conversion is a known underlying factor in sea level pregnancies complicated by both IUGR and early onset pre-eclampsia. In this issue of The Journal of Physiology, Hu and colleagues (2018) discover deeper novel molecular mechanisms promoting the increased vascular resistance of uterine arteries in an ovine model of high altitude pregnancy. The authors elegantly demonstrate a causal role for miR-210 in downregulating ten–eleven translocation methylcytosine dioxygenase 1 (TET1) in uterine arteries of pregnant sheep at high altitude, and they mechanistically link this cross-talk to the large conductance Ca2+-activated K+ (BKCa) channel dysfunction in uterine arteries under chronic hypoxia. Hu and colleagues also show that blocking miR-210 ameliorates the hypoxia-induced reduction in TET1 and the consequent suppression of BKCa channel B1 subunit function, thereby restoring appropriate uterine blood flow. Therefore, this cutting-edge study identifies miR-210 as a potential therapeutic target that could protect utero-placental perfusion and fetal growth in a myriad of pathological pregnancy conditions associated with increased uterine vascular resistance, such as in pregnancy at high altitude or in sea level pregnancies complicated by IUGR or pre-eclampsia.