Establishment of the maternal-fetal interface is critically important since is at this level that uteroplacental and fetoplacental blood flows are regulated, and dysfunction is associated with diseases of pregnancy, e.g. preeclampsia. We observed a central role for Gap junctions and specifically Gx4S assembly in enabling pregnancy adaptation of endothelial vasodilatory capacity. We now provide evidence that it may be altered quite negatively by the numerous chemokine's reported to be secreted by the trophoblast. cAMP/cGMP as well as shear stress is also implicated by our studies to promote Gap junction formation for endothelial cell-cell communication. Under chronic hypoxic conditions (preeclampsia), increases in growth factors and inflammatory cytokines e.g. VEGF and TNF are reported to cause severe detrimental alterations in the functional angiogenic and NO synthetic responses to VEGF and FGF2 via alterations in specific G-protein coupling transducers (GNA14 and GNA14). The central theme of this POl is that cell-cell communication between endothelial cells underlies normal functions and that the high levels of growth factors and cytokines (VEGF &TNF) released in preeclampsia will disrupt Gap junction assembly/function thus compromising vasodilator and angiogenic function. We also explore therapeutic strategies to reverse Gap junction dysfunction. Project I ERK and Src as negative regulators of pregnancy adapted uterine artery endothelial function. Project II Shear stress and Gap junction-mediated pregnancy adaptations of uterine artery and human umbilical vessel endothelial cell function. Project III the roles of GNA14 and GNA11 in human fetal endothelial cell function. Continuing strong synergy of these projects is facilitated through leadership in the Administrative core (Gore A) and efficient utilization of the Live Cell Imaging and Protein Analytical Gore B and Cell and Immunocytochemistry Gore G. Interactions between with Projects will also provide novel insights into cell-cell communication between endothelial cells, so providing a much deeper understanding of the inter/intracellular mechanisms in normal and abnormal pregnancies (e.g. preeclampsia).

Public Health Relevance

The studies represent major advancements in understanding the effects of uterine and placental endothelial adaptation via Gap junction-mediated cell-cell communication at the maternal fetal interface. This leads to indepth understanding of the inter/intracellular mechanisms at the maternal-fetal interface in normal and abnormal pregnancies (e.g. preeclampsia with lUGR).

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD038843-12
Application #
8720794
Study Section
Special Emphasis Panel (ZHD1-DSR-Z (MR))
Program Officer
Ilekis, John V
Project Start
2000-04-01
Project End
2018-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
12
Fiscal Year
2014
Total Cost
$911,570
Indirect Cost
$299,379
Name
University of Wisconsin Madison
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Schreier, David A; Forouzan, Omid; Hacker, Timothy A et al. (2016) Increased Red Blood Cell Stiffness Increases Pulmonary Vascular Resistance and Pulmonary Arterial Pressure. J Biomech Eng 138:021012
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
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
Rozner, Ann E; Durning, Maureen; Kropp, Jenna et al. (2016) Macrophages modulate the growth and differentiation of rhesus monkey embryonic trophoblasts. Am J Reprod Immunol 76:364-375
Li, Yan; Wang, Kai; Zou, Qing-Yun et al. (2015) 2,3,7,8-Tetrachlorodibenzo-p-dioxin differentially suppresses angiogenic responses in human placental vein and artery endothelial cells. Toxicology 336:70-8
Morris, Erin A; Hale, Sarah A; Badger, Gary J et al. (2015) Pregnancy induces persistent changes in vascular compliance in primiparous women. Am J Obstet Gynecol 212:633.e1-6
Boeldt, Derek S; Grummer, Mary A; Yi, FuXian et al. (2015) Phosphorylation of Ser-279/282 and Tyr-265 positions on Cx43 as possible mediators of VEGF-165 inhibition of pregnancy-adapted Ca2+ burst function in ovine uterine artery endothelial cells. Mol Cell Endocrinol 412:73-84
Li, Yan; Wang, Kai; Zou, Qing-Yun et al. (2015) A possible role of aryl hydrocarbon receptor in spontaneous preterm birth. Med Hypotheses 84:494-7
Ampey, Bryan; Bird, Ian; Magness, Ron (2015) [307-POS]: Cx43 phosphorylation and the functionality of Cx43 gap junctions are moderated by cyclic nucleotide activity in UAECs and HUVECs. Pregnancy Hypertens 5:151-2
Anaya, Heather A; Yi, Fu-Xian; Boeldt, Derek S et al. (2015) Changes in Ca2+ Signaling and Nitric Oxide Output by Human Umbilical Vein Endothelium in Diabetic and Gestational Diabetic Pregnancies. Biol Reprod 93:60

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