The maternal-fetal interface is critically important since is at this level that uteroplacental and fetoplacental blood flows are regulated and dysfunctions are seen in diseases of pregnancy, e.g. preeclampsia. Vasodilation is controlled by PGI2 and Nitric Oxide (NO) of endothelial origin and locally shows obligatory requirements for cell-cell communication via Gap junctions, a common theme in this PO-1. Uterine Artery Endothelial Cells in Pregnancy (P-UAEC) and HUVECs undergo "Programmed Adaptation" to maintain NO production via a Connexin (Cx) 43 mediated mechanisms. HYPOTHESIS Aim 1: Endothelial "Programmed Adaptation" is modulated by the Gap junction protein Cx43 that is elevated directly by Shear Stress via cAMP and/or cGMP to maintain vasodilator (PGI2 and NO) production. Purpose Aim 1: To determine in P-UAECs, HUVECs and HUAECs the effects of: 1) acute vs. prolonged Laminar Shear Stress on levels of phosphorylated and total Cx43 &eNOS and vasodilator production (PGI2 and NO) relative to cyclic nucleotide (cAMP and cGMP) adaptation;2) inhibition of PKA, PKG, Adenylate Cyclase and sol Guanylate Cyclase;and 3) Indomethacin and L-NAME on these shear stress responses. HYPOTHESIS Aim 2: These important shear stress-mediated vasodilator mechanisms are abrogated by patho-physiologic levels of representative cytokines elevated in preeclampsia [VEGF and Tumor Necrosis Factor] via functional Gap junction disruption. We hypothesize that shear stress elevates cAMP /cGMP which is "protective" for maintaining vasodilator production via Gap junction assembly. Purpose Aim 2: To determine in P-UAECs, HUVECs and HUAECs if these cytokines disrupt the shear stress-associated cyclic nucleotide Gap junction-mediated vasodilator mechanisms we will evaluate: 1) effects of treatment with VEGF and TNF on the acute and prolonged laminar shear stress responses;2) the "therapeutic protective" effects 8-Br-cAMP and 8-Br-cGMP on VEGF and TNF disruption of shear stress responses;and 3) the "therapeutic protective" effects cAMP phosphodiesterase (PDE)2, cAMP PDES, cAMP PDE4, or cGMP PDE5 inhibitors on VEGF and TNF disruption of shear stress responses. These data provide the first mechanistic framework for understanding the interactions between shear stress-mediated cyclic nucleotides for "therapeutic protective actions" and Gap junctions to regulate endothelial vasodilator (PGI2 &NO) production and it's abrogation via cytokine (VEGF &TNF) mediated disruption of cell-cell communication.
These studies represent major advancements in understanding the protective (therapeutic) effects of shear stress mediators on molecular/signaling mechanisms regulating uterine and placental endothelial adaptation via Gap junction-mediated cell-cell communication at the maternal-fetal interface. These mechanisms underlying uterine and placental endothelial vasodilator (PGI2 and NO) dysfunction caused by cytokines (VEGF and TNF) in preeclampsia and their abrogation by shear stress induced cAMP/cGMP.
|Boeldt, Derek S; Hankes, Amanda C; Alvarez, Roxanne E et al. (2014) Pregnancy programming and preeclampsia: identifying a human endothelial model to study pregnancy-adapted endothelial function and endothelial adaptive failure in preeclamptic subjects. Adv Exp Med Biol 814:27-47|
|Zhao, Ying-Jie; Zou, Qing-Yun; Li, Yan et al. (2014) Expression of G-protein subunit ?-14 is increased in human placentas from preeclamptic pregnancies. J Histochem Cytochem 62:347-54|
|Jiang, Yi-Zhou; Li, Yan; Wang, Kai et al. (2014) Distinct roles of HIF1A in endothelial adaptations to physiological and ambient oxygen. Mol Cell Endocrinol 391:60-7|
|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|
|Chen, Dong-Bao; Zheng, Jing (2014) Regulation of placental angiogenesis. Microcirculation 21:15-25|
|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|
|Boeldt, Derek S; Grummer, Mary A; Magness, Ronald R et al. (2014) Altered VEGF-stimulated Ca2+ signaling in part underlies pregnancy-adapted eNOS activity in UAEC. J Endocrinol 223:1-11|
|Schreier, David A; Hacker, Timothy A; Hunter, Kendall et al. (2014) Impact of increased hematocrit on right ventricular afterload in response to chronic hypoxia. J Appl Physiol (1985) 117:833-9|
|Morschauser, Timothy J; Ramadoss, Jayanth; Koch, Jill M et al. (2014) Local effects of pregnancy on connexin proteins that mediate Ca2+-associated uterine endothelial NO synthesis. Hypertension 63:589-94|
|Giakoumopoulos, M; Golos, T G (2013) Embryonic stem cell-derived trophoblast differentiation: a comparative review of the biology, function, and signaling mechanisms. J Endocrinol 216:R33-45|
Showing the most recent 10 out of 53 publications