Hypoxia reduces placental mTOR activation in a hypoxia-induced model of intrauterine growth restriction (IUGR)

Kimball, Rebecca Lutz; Wayment, Montana; Merrill, Daniel; Wahlquist, Tyler; Reynolds, Paul; Arroyo, Juan A.

doi:10.14814/phy2.12651

Cited by 22 publications

(15 citation statements)

References 44 publications

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“…2). Studies of human pregnancy at high altitude and in several animal models of maternal exposure to chronic hypoxia have confirmed that gestational hypoxia leads to significant FGR [54][55][56][57] (Fig. 2).…”

Section: Effects Of Maternal Hypoxia On the Fetoplacental Unitmentioning

confidence: 79%

Preeclampsia link to gestational hypoxia

Tong

Giussani

2019

J Dev Orig Health Dis

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Complications of pregnancy remain key drivers of morbidity and mortality, affecting the health of both the mother and her offspring in the short and long term. There is lack of detailed understanding of the pathways involved in the pathology and pathogenesis of compromised pregnancy, as well as a shortfall of effective prognostic, diagnostic and treatment options. In many complications of pregnancy, such as in preeclampsia, there is an increase in uteroplacental vascular resistance. However, the cause and effect relationship between placental dysfunction and adverse outcomes in the mother and offspring remains uncertain. In this review, we aim to highlight the value of gestational hypoxia-induced complications of pregnancy in elucidating underlying molecular pathways and in assessing candidate therapeutic options for these complex disorders. Chronic maternal hypoxia not only mimics the placental pathology associated with obstetric syndromes like gestational hypertension at morphological, molecular and functional levels, but it also recapitulates key symptoms that occur as maternal and fetal clinical manifestations of these pregnancy disorders. We propose that gestational hypoxia provides a useful model to study the inter-relationship between placental dysfunction and adverse outcomes in the mother and offspring in a wide array of examples of complicated pregnancy, such as in preeclampsia.

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Section: Effects Of Maternal Hypoxia On the Fetoplacental Unitmentioning

confidence: 79%

Preeclampsia link to gestational hypoxia

Tong

Giussani

2019

J Dev Orig Health Dis

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“…This can be attributed to an HPX-induced increase in placenta tissue volume [ 36 ] and an increase in both blood spaces and vessel diameters in the labyrinth. Others reported increased [ 37 , 38 ], decreased [ 39 ], and no change [ 36 , 40 ] in placental weight with HPX, identifying differences in hypoxic severity, timing of gestation, and animal species. Despite the increased placental weight, fetal body weight is decreased compared to their NMX controls, clearly indicating an inefficient placenta.…”

Section: Discussionmentioning

confidence: 99%

Placental Hypoxia During Early Pregnancy Causes Maternal Hypertension and Placental Insufficiency in the Hypoxic Guinea Pig Model

Thompson

Pence

Pinkas

et al. 2016

Biology of Reproduction

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Chronic placental hypoxia is one of the root causes of placental insufficiencies that result in pre-eclampsia and maternal hypertension. Chronic hypoxia causes disruption of trophoblast (TB) development, invasion into maternal decidua, and remodeling of maternal spiral arteries. The pregnant guinea pig shares several characteristics with humans such as hemomonochorial placenta, villous subplacenta, deep TB invasion, and remodeling of maternal arteries, and is an ideal animal model to study placental development. We hypothesized that chronic placental hypoxia of the pregnant guinea pig inhibits TB invasion and alters spiral artery remodeling. Time-mated pregnant guinea pigs were exposed to either normoxia (NMX) or three levels of hypoxia (HPX: 16%, 12%, or 10.5% O2) from 20 day gestation until midterm (39–40 days) or term (60–65 days). At term, HPX (10.5% O2) increased maternal arterial blood pressure (HPX 57.9 ± 2.3 vs. NMX 40.4 ± 2.3, P < 0.001), decreased fetal weight by 16.1% (P < 0.05), and increased both absolute and relative placenta weights by 10.1% and 31.8%, respectively (P < 0.05). At midterm, there was a significant increase in TB proliferation in HPX placentas as confirmed by increased PCNA and KRT7 staining and elevated ESX1 (TB marker) gene expression (P < 0.05). Additionally, quantitative image analysis revealed decreased invasion of maternal blood vessels by TB cells. In summary, this animal model of placental HPX identifies several aspects of abnormal placental development, including increased TB proliferation and decreased migration and invasion of TBs into the spiral arteries, the consequences of which are associated with maternal hypertension and fetal growth restriction.

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“…Enhanced oxidative stress leads to abnormal endoplasmic reticular (ER) function, resulting in trophoblast autophagy, autophagic vacuole formation and cellular apoptosis. These processes are associated with fetal growth restriction and are particularly more pronounced when trophoblasts are exposed to reduced oxygen tensions or nutrientdepleted environments (Curtis et al 2013, Kimball et al 2015. Endoplasmic stress and protein synthesis blockage have also been demonstrated in women living at high altitudes, exposed to chronic hypoxia (Yung et al 2012a).…”

Section: Er Stress/autophagy/apoptosismentioning

confidence: 99%

Nutrient sensor signaling pathways and cellular stress in fetal growth restriction

Hart

Morgan

Alejandro

2019

Journal of Molecular Endocrinology

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Fetal growth restriction is one of the most common obstetrical complications resulting in significant perinatal morbidity and mortality. The most frequent etiology of human singleton fetal growth restriction is placental insufficiency, which occurs secondary to reduced utero-placental perfusion, abnormal placentation, impaired trophoblast invasion and spiral artery remodeling, resulting in altered nutrient and oxygen transport. Two nutrient-sensing proteins involved in placental development and glucose and amino acid transport are mechanistic target of rapamycin (mTOR) and O-linked N-acetylglucosamine transferase (OGT), which are both regulated by availability of oxygen. Impairment in either of these pathways is associated with fetal growth restriction and accompanied by cellular stress in the forms of hypoxia, oxidative and endoplasmic reticulum (ER) stress, metabolic dysfunction and nutrient starvation in the placenta. Recent evidence has emerged regarding the potential impact of nutrient sensors on fetal stress response, which occurs in a sexual dysmorphic manner, indicating a potential element of genetic gender susceptibility to fetal growth restriction. In this mini review, we focus on the known role of mTOR and OGT in placental development, nutrient regulation and response to cellular stress in human fetal growth restriction with supporting evidence from rodent models.

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Hypoxia reduces placental mTOR activation in a hypoxia-induced model of intrauterine growth restriction (IUGR)

Cited by 22 publications

References 44 publications

Preeclampsia link to gestational hypoxia

Preeclampsia link to gestational hypoxia

Placental Hypoxia During Early Pregnancy Causes Maternal Hypertension and Placental Insufficiency in the Hypoxic Guinea Pig Model

Nutrient sensor signaling pathways and cellular stress in fetal growth restriction

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