During early human pregnancy, placental extravillous cytotrophoblasts (EVT) migrate to, invade and remodel the uterine spiral arteries transforming them from high resistance low capacity to low resistance high capacity vessels. Improper vascular invasion may lead to miscarriage and complications, e.g. preeclampsia, that result in neonatal morbidity and mortality, indicating need for intensive study of this area of perinatal biology. Vascular endothelial growth factor (VEGF), by modulating expression of extracellular matrix(ECM) receptors, i.e. integrins, and cell adhesion molecules (CAM) and matrix metalloproteinases(MMP), has been shown in vitro to play an important role in vascular invasion. However, little is known about the regulation of EVT expression of VEGF and ECM molecules or vessel invasion. Because most of this research has been conducted in vitro, translation in vivo to the human is unproven. Importantly, it is assumed but not established that uterine artery remodeling promotes blood flow to and growth of the placenta and fetus. We have recently shown that advancing the surge in estrogen from the second to the first trimester of baboon gestation suppressed uterine artery invasion. This unique primate experimental model and novel finding should lead to new insight into the regulation of uteroplacental vessel remodeling and impact on placental- fetal blood flow and growth. We propose that the low level of endogenous estrogen in early gestation ensures normal EVT spiral artery invasion and the increase in estrogen during advancing pregnancy regulates the extent to which uterine arteries are remodeled by inhibiting EVT VEGF (and ECM molecule) expression.
Specific Aim 1 will test the hypothesis that during early pregnancy estrogen suppresses EVT expression of VEGF, integrins, CAM, and/or MMP important for uterine artery invasion. Spiral artery invasion and mRNA/protein levels of VEGF-A, VEGF-C, sflt-1, a1(31, a5(31, av(33, PECAM, VCAM, MMP-2, and MMP- 9 will be quantified in EVT isolated on day 60 of gestation (term is 184 days) from baboons untreated or treated on days 25-59 with estradiol or on day 100 after administration of the aromatase inhibitor CGS 20267 on days 60-99. In vivo and in vitro experiments will determine whether temporal and modulatory links exists between acute estradiol injection of baboons, VEGF and ECM molecule expression, and EVT migration.
Specific Aim 2 will test the hypothesis that estrogen, by suppressing artery invasion, alters blood flow to and growth of the placenta and fetus. Uteroplacental and fetal blood flow and growth assessed by Dpppler ultrasonography and placental and fetal biochemical/ rnolecular/morphometric parameters sensitive to hypoxia will be determined on days 40-170 in baboons untreated or treated with estradiol on days 25-59. This study focuses on a significant area of biomedical research, elucidates the actions of estrogen in pregnancy using an established nonhuman primate with important translational value to the human, permits an integrated investigation of placental and fetal development, and combines in vivo and in vitro experimental approaches. This study is expected to conceptually advance knowledge of the regulation of spiral artery invasion and ultimately lead to new approaches to address the high incidence of pregnancy disorders that stem from improper remodeling of the uteroplacental vascular bed.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Pregnancy and Neonatology Study Section (PN)
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Ilekis, John V
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University of Maryland Baltimore
Obstetrics & Gynecology
Schools of Medicine
United States
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Bonagura, Thomas W; Babischkin, Jeffery S; Pepe, Gerald J et al. (2016) Assessment of Protein Expression by Proximity Ligation Assay in the Nonhuman Primate Endometrium, Placenta, and Fetal Adrenal in Response to Estrogen. Methods Mol Biol 1366:149-161
Dumitrescu, Adina; Aberdeen, Graham W; Pepe, Gerald J et al. (2014) Placental estrogen suppresses cyclin D1 expression in the nonhuman primate fetal adrenal cortex. Endocrinology 155:4774-84
Pepe, Gerald J; Lynch, Terrie J; Albrecht, Eugene D (2013) Regulation of baboon fetal ovarian development by placental estrogen: onset of puberty is delayed in offspring deprived of estrogen in utero. Biol Reprod 89:132
Bonagura, Thomas W; Babischkin, Jeffery S; Aberdeen, Graham W et al. (2012) Prematurely elevating estradiol in early baboon pregnancy suppresses uterine artery remodeling and expression of extravillous placental vascular endothelial growth factor and ?1?1 and ?5?1 integrins. Endocrinology 153:2897-906
Aberdeen, Graham W; Bonagura, Thomas W; Harman, Chris R et al. (2012) Suppression of trophoblast uterine spiral artery remodeling by estrogen during baboon pregnancy: impact on uterine and fetal blood flow dynamics. Am J Physiol Heart Circ Physiol 302:H1936-44
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