Trophoblast-Specific Expression of Hif-1α Results in Preeclampsia-Like Symptoms and Fetal Growth Restriction

Abstract

The placenta is an essential organ that is formed during pregnancy and its proper development is critical for embryonic survival. While several animal models have been shown to exhibit some of the pathological effects present in human preeclampsia, these models often do not represent the physiological aspects that have been identified. Hypoxia-inducible factor 1 alpha (Hif-1α) is a necessary component of the cellular oxygen-sensing machinery and has been implicated as a major regulator of trophoblast differentiation. Elevated levels of Hif-1α in the human placenta have been linked to the development of pregnancy-associated disorders, such as preeclampsia and fetal growth restriction. As oxygen regulation is a critical determinant for placentogenesis, we determined the effects of constitutively active Hif-1α, specifically in trophoblasts, on mouse placental development in vivo . Our research indicates that prolonged expression of trophoblast-specific Hif-1α leads to a significant decrease in fetal birth weight. In addition, we noted significant physiological alterations in placental differentiation that included reduced branching morphogenesis, alterations in maternal and fetal blood spaces, and failure to remodel the maternal spiral arteries. These placental alterations resulted in subsequent maternal hypertension with parturitional resolution and maternal kidney glomeruloendotheliosis with accompanying proteinuria, classic hallmarks of preeclampsia. Our findings identify Hif-1α as a critical molecular mediator of placental development and indicate that prolonged expression of Hif-1α, explicitly in placental trophoblasts causes maternal pathology and establishes a mouse model that significantly recapitulates the physiological and pathophysiological characteristics of preeclampsia with fetal growth restriction.

Δ9-tetrahydrocannabinol exposure during rat pregnancy leads to symmetrical fetal growth restriction and labyrinth-specific vascular defects in the placenta

“…Like other models of placental insufficiency that identify changes in the relative size of placental layers 64,65,90 , this study identifies that placentae from pregnancies exposed to Δ9-THC exhibited changes in the labyrinth layer, but not in the junctional zone. While proliferation at E19.5 was not the cause for the increased area of the www.nature.com/scientificreports www.nature.com/scientificreports/ labyrinth layer from these pregnancies, there is the possibility that there was proliferation of trophoblast and endothelial cells at an earlier time in gestation, which may have contributed to the altered size.…”

“…The labyrinth zone is the site of maternal-fetal exchange and alterations in vascular development are critical and can contribute to fetal growth restriction. To explore whether the fetal growth restriction observed in Δ9-THC pups could be attributed to placental insufficiency, the fetal capillary network and maternal blood sinusoids within the labyrinth layer (herein referred to as fetal and maternal blood spaces, respectively), were assessed [62][63][64][65] . The assessment included: area of blood spaces as a percentage of the field of view; maternal to fetal blood space ratio and the perimeter to area ratio, all indicators of surface available for nutrient exchange.…”

Increased Angiogenesis and Lymphangiogenesis in the Placental Villi of Women with Chronic Venous Disease during Pregnancy

“…We have previously shown that lower extremity CVD during pregnancy is associated with some placental changes, such as extracellular matrix remodelling or increased placental apoptosis and villous calcification, along with increased expression of tissue hypoxia markers [10][11][12]. These mechanisms are also dysregulated at the placental level in other important vascular diseases, such as preeclampsia and intrauterine foetal growth restriction [13][14][15]. It should be highlighted how all these pathological conditions affect the process of angiogenesis.…”

Sleep disordered breathing in pregnancy: A review of the pathophysiology of adverse pregnancy outcomes

“…It is composed of HIF‐1α and HIF‐1β subunits. Under normoxic conditions, HIF‐1α is rapidly degraded and inactivated . In hypoxia, HIF‐1α is activated and regulates the cellular response by promoting the expression of a wide variety of genes .…”

“…HIF‐1α has been established as a key regular of placental development, specifically trophoblast differentiation . Elevated placental HIF‐1α levels are evident in pre‐eclampsia and are hypothesized to contribute to the pathogenesis of this condition through downstream effects on angiogenic proteins, including upregulation of soluble fms‐like tyrosine kinase 1 (sFlt1) and downregulation of placental growth factor (PlGF) . Serum HIF‐1α levels were significantly higher in males with severe OSA compared to controls and those with mild and moderate disease, returning towards normal following CPAP therapy .…”