Department of Physiology Development & Neuroscience, University of Cambridge, United Kingdom (W.T., B.J.A., K.L.B., O.V.P., Y.N., K.J.B., S.G.F., T.A.G., P.F.B.W., T.C.-D., H.W.Y., G.J.B., D.A.G.).
Centre for Trophoblast Research, University of Cambridge, United Kingdom (W.T., Y.N., K.J.B., T.A.G., P.G.B.W., T.C.-D., H.W.Y., G.J.B., D.A.G.).
Hypertension. 2022 Jul;79(7):1525-1535. doi: 10.1161/HYPERTENSIONAHA.122.19175. Epub 2022 May 9.
Preeclampsia continues to be a prevalent pregnancy complication and underlying mechanisms remain controversial. A common feature of preeclampsia is utero-placenta hypoxia. In contrast to the impact of hypoxia on the placenta and fetus, comparatively little is known about the maternal physiology.
We adopted an integrative approach to investigate the inter-relationship between chronic hypoxia during pregnancy with maternal, placental, and fetal outcomes, common in preeclampsia. We exploited a novel technique using isobaric hypoxic chambers and in vivo continuous cardiovascular recording technology for measurement of blood pressure in sheep and studied the placental stress in response to hypoxia at cellular and subcellular levels.
Chronic hypoxia in ovine pregnancy promoted fetal growth restriction (FGR) with evidence of fetal brain-sparing, increased placental hypoxia-mediated oxidative damage, and activated placental stress response pathways. These changes were linked with dilation of the placental endoplasmic reticulum (ER) cisternae and increased placental expression of the antiangiogenic factors sFlt-1 (soluble fms-like tyrosine kinase 1) and sEng (soluble endoglin), combined with a shift towards an angiogenic imbalance in the maternal circulation. Chronic hypoxia further led to an increase in uteroplacental vascular resistance and the fall in maternal blood pressure with advancing gestation measured in normoxic pregnancy did not occur in hypoxic pregnancy.
Therefore, we show in an ovine model of sea-level adverse pregnancy that chronic hypoxia recapitulates physiological and molecular features of preeclampsia in the mother, placenta, and offspring.
子痫前期仍然是一种普遍的妊娠并发症，其潜在机制仍存在争议。子痫前期的一个共同特征是子宫胎盘缺氧。与缺氧对胎盘和胎儿的影响相比，人们对母体生理学的了解相对较少。
我们采用综合方法研究了与子痫前期常见的妊娠期间慢性缺氧与母体、胎盘和胎儿结局之间的相互关系。我们利用等压缺氧室和体内连续心血管记录技术的新技术来测量绵羊的血压，并研究了细胞和亚细胞水平上胎盘对缺氧的应激反应。
绵羊妊娠慢性缺氧促进胎儿生长受限（FGR），并伴有胎儿脑保护的证据，增加了胎盘缺氧介导的氧化损伤，并激活了胎盘应激反应途径。这些变化与胎盘内质网（ER）腔扩张和胎盘抗血管生成因子 sFlt-1（可溶性 fms 样酪氨酸激酶 1）和 sEng（可溶性内皮）的表达增加有关，同时母体循环中的血管生成失衡也发生了转变。慢性缺氧进一步导致胎盘血管阻力增加，而在正常妊娠中随着妊娠进展血压下降的情况在缺氧妊娠中并未发生。
因此，我们在海平面不良妊娠的绵羊模型中表明，慢性缺氧再现了母亲、胎盘和后代子痫前期的生理和分子特征。
