Interactions between estrogen and NO production are significant since dysfunctions are noted in Preeclampsia with IUGR. Pregnancy-induced rises in UBF were significantly inhibited (35-40%) by Estrogen Receptor (ER) antagonist, ICI 182,780 and NOS inhibitor L-NAME suggesting cause and effect relationships exists between endogenous ER activation and DA endothelial NO production. We will focus on third trimester pregnancies testing the overall hypothesis that estrogen is maintains normal CV adaptations via both eNOS levels and NO production at the level of the Uterine Artery endothelium.
Specific Aim 1 : Development of an Ovine Animal Model of Endogenous Estrogen Blockade Using Letrozole (CGS 20267); IC1182,78, L-NAME and DHEA effects:
Specific Aim II : ln_Vivo: Physiological cardiovascular adaptation (Peripheral, Cardiac and Uterine) and Hormonal (steroid hormones, cGMP and Nitric Oxide Metabolites (NOx) Changes in Letrozole-treated Pregnant Sheep:
Specific Aim III : Ex Vivo/In Vitro: Mechanistic Cellular and Molecular Signaling Changes in Uterine Arteries from Vehicle and Letrozole-treated Pregnant Sheep: a) Ability of the UA endothelium to produce basal and stimulated (ATP and lonomycin) NOand the role of initial and sustained [Ca2+ ] bursts in this response. Specific mechanistic roles of estrogen receptors, shear stress, and the ERK-1/2 and PI3 Kinase AKT signaling pathways will be evaluated. Because regulation of UBF is mandatory for providing proper delivery of nutrients and oxygen to the developing fetus these vasodilator mechanisms have significant impacts on fetal growth and development. Data generated with the aromatase inhibitor Letrozole will directly define the role of placental estrogen produced at the maternal: fetal interface in regulating uteroplacental blood flows.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL087144-02S1
Application #
7635379
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Barouch, Winifred
Project Start
2007-09-01
Project End
2011-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
2
Fiscal Year
2008
Total Cost
$167,991
Indirect Cost
Name
University of Wisconsin Madison
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Zywicki, Micaela E; Blohowiak, Sharon E; Magness, Ronald R et al. (2018) Impact of the ovarian cycle and pregnancy on plasma chemistry values in ewes. J Vet Diagn Invest 30:238-244
Kranch-Shorthouse, Rachel A; Bauer, Adam S; Magness, Ronald R et al. (2017) Ovine uterine space restriction causes dysregulation of the renin-angiotensin system in fetal kidneys. Biol Reprod 96:211-220
Landeros, Rosalina Villalon; Jobe, Sheikh O; Aranda-Pino, Gabrielle et al. (2017) Convergent ERK1/2, p38 and JNK mitogen activated protein kinases (MAPKs) signalling mediate catecholoestradiol-induced proliferation of ovine uterine artery endothelial cells. J Physiol 595:4663-4676
Vargas, Vladimir E; Landeros, Rosalina Villalon; Lopez, Gladys E et al. (2017) Uterine artery leptin receptors during the ovarian cycle and pregnancy regulate angiogenesis in ovine uterine artery endothelial cells†. Biol Reprod 96:866-876
Pastore, Mayra B; Talwar, Saira; Conley, Meghan R et al. (2016) Identification of Differential ER-Alpha Versus ER-Beta Mediated Activation of eNOS in Ovine Uterine Artery Endothelial Cells. Biol Reprod 94:139
Ampey, Bryan C; Morschauser, Timothy J; Ramadoss, Jayanth et al. (2016) Domain-Specific Partitioning of Uterine Artery Endothelial Connexin43 and Caveolin-1. Hypertension 68:982-8
Sun, Mary Y; Woolley, Joseph C; Blohowiak, Sharon E et al. (2016) Dietary-induced gestational iron deficiency inhibits postnatal tissue iron delivery and postpones the cessation of active nephrogenesis in rats. Reprod Fertil Dev :
Mayra, Pastore R; Rosalina, Villalón L; López, Gladys et al. (2014) [Regulation of uterine blood flow. I. Functions of estrogen and estrogen receptor ?/? in the uterine vascular endothelium during pregnancy]. Rev Chil Obstet Ginecol 79:129-139
Ampey, Bryan C; Morschauser, Timothy J; Lampe, Paul D et al. (2014) Gap junction regulation of vascular tone: implications of modulatory intercellular communication during gestation. Adv Exp Med Biol 814:117-32
Li, Hui-Hui; Zhao, Ying-Jie; Li, Yan et al. (2014) Estradiol 17? and its metabolites stimulate cell proliferation and antagonize ascorbic acid-suppressed cell proliferation in human ovarian cancer cells. Reprod Sci 21:102-11

Showing the most recent 10 out of 36 publications