We seek to develop and characterize the world's only in-vivo model of human placentation under conditions of chronic hypoxia. Using the unique model of high altitude human pregnancy, the goal of this project is to examine the pathways by which hypoxia, in the absence of pathology, influences placental development and results in adaptation (i.e. normal growth) or fetal growth restriction. In vitro experiments show that oxygen plays a crucial role in early placental development and that both oxygen tension and the time at which it increases are key factors in determining the success of placentation. This data and clinical observations make it clear that hypoxia plays a major role in those pathologies involving abnormalities of placental development, such as intrauterine growth restriction and preeclampsia. Unfortunately, hypoxia is inevitably intertwined with under- or overlying pathologies and thus it has not been possible to investigate the role of hypoxia in placental development in vivo in the absence of pathology. We predict that the initial effect of chronic maternal hypoxia due to high altitude residence (3600 m) is reduction in trophoblast invasion of uteroplacental arteries, leading to a reduction in uteroplacental blood flow. Subsequent to this, our preliminary data suggest that there are two primary placental responses. The first is an up regulation of angiogenesis reflected in greater placental capillary density and increased release of angiogenic growth factors. The second is a decrease in placental nutrient transport and a consequent down-regulation of fetal growth and placental nutrient transport capacity.
The aims of the project are to investigate these responses by determining whether, in high vs. low altitude pregnancy 1) there are increased circulating and placental markers of hypoxia, correlated with reduced trophoblast invasion and uteroplacental blood flow; 2) an increased angiogenic response, as evidenced by placental morphologic changes and increases in circulating and placental angiogenic growth factors, and 3) decreased nutrient transfer, decreased circulating growth factors and reduced placental nutrient transporter capacity. Gene array is used across all 3 aims to investigate 4 groups of specifically targeted and functionally essential genes 1) hypoxia-responsive genes, 2) gene markers of trophoblast invasion, 3) markers of angiogenesis and 4) nutrient transporters and transport regulators. This model will permit the development of a foundation upon which the etiology of various forms of IUGR can be explored. Such work will aid substantially in elucidating the pathologies that involve placenta hypoxia, e.g., preeclampsia, diabetes and IUGR.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD042737-01A1
Application #
6687413
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Ilekis, John V
Project Start
2003-08-01
Project End
2007-05-31
Budget Start
2003-08-01
Budget End
2004-05-31
Support Year
1
Fiscal Year
2003
Total Cost
$270,709
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
623946217
City
Newark
State
NJ
Country
United States
Zip Code
07107
Francois, Lissa N; Gorczyca, Ludwik; Du, Jianyao et al. (2017) Down-regulation of the placental BCRP/ABCG2 transporter in response to hypoxia signaling. Placenta 51:57-63
Zamudio, Stacy; Borges, Marcus; Echalar, Lourdes et al. (2014) Maternal and fetoplacental hypoxia do not alter circulating angiogenic growth effectors during human pregnancy. Biol Reprod 90:42
Zamudio, S; Kovalenko, O; Echalar, L et al. (2013) Evidence for extraplacental sources of circulating angiogenic growth effectors in human pregnancy. Placenta 34:1170-6
Williams, S F; Fik, E; Zamudio, S et al. (2012) Global protein synthesis in human trophoblast is resistant to inhibition by hypoxia. Placenta 33:31-8
Zamudio, Stacy; Torricos, Tatiana; Fik, Ewa et al. (2010) Hypoglycemia and the origin of hypoxia-induced reduction in human fetal growth. PLoS One 5:e8551
Illsley, Nicholas P; Caniggia, Isabella; Zamudio, Stacy (2010) Placental metabolic reprogramming: do changes in the mix of energy-generating substrates modulate fetal growth? Int J Dev Biol 54:409-19
Postigo, Lucrecia; Heredia, Gladys; Illsley, Nicholas P et al. (2009) Where the O2 goes to: preservation of human fetal oxygen delivery and consumption at high altitude. J Physiol 587:693-708
Zamudio, Stacy; Wu, Yuanhong; Ietta, Francesca et al. (2007) Human placental hypoxia-inducible factor-1alpha expression correlates with clinical outcomes in chronic hypoxia in vivo. Am J Pathol 170:2171-9
Zamudio, Stacy; Postigo, Lucrecia; Illsley, Nicholas P et al. (2007) Maternal oxygen delivery is not related to altitude- and ancestry-associated differences in human fetal growth. J Physiol 582:883-95
Ietta, Francesca; Wu, Yuanhong; Romagnoli, Roberta et al. (2007) Oxygen regulation of macrophage migration inhibitory factor in human placenta. Am J Physiol Endocrinol Metab 292:E272-80

Showing the most recent 10 out of 20 publications