Actions of Estrogen on Uterine Artery Endothelium

Summary

Principal Investigator: DongBao Chen
Affiliation: University of California
Country: USA
Abstract: The hypothesis of this renewal grant is that, on binding to estrogen receptors (i.e., ERa and ER(3) on the plasma membranes, estrogen rapidly activates receptor subtype-specific intracellular signaling pathways (i.e., G-proteins) leading to endothelial nitric oxide (NO) synthase (eNOS) and extracellular signal-regulated kinases (ERK2/1) activation. Translocation of activated ERK2/1 stimulates the AP-1 (Jun/Fos dimers) transcription factors in the nucleus where they interact with ERa and ERp to reciprocally regulate eNOS and caveolin-1 expression by estrogen. Five specific aims will be studied by using the well-defined sheep uterine artery endothelial cell culture model and human umbilical cord vein endothelial cells. Aim 1: to determine the proximal membrane ER signaling events (G-protein activation) and if ERa and ERb play different roles in G-protein activation and eNOS-NO production and ERK2/1 pathway on estrogen stimulation. Aim 2: to determine if membrane and nuclear ERa and ERb are both involved in the reciprocal regulation of eNOS and caveolin-1 mRNA and protein expression by estrogen. Aim 3: to determine the role of c-Jun/Jun-B AP-1 in regulating eNOS and caveolin-1 expression by estrogen. Aim 4: to determine the transcriptional mechanism(s) underlying estrogen stimulation of endothelial eNOS expression, i.e., activation of eNOS promoter via ERa and ERb interaction with AP-1. Aim 5: to determine the mechanisms underlying down-regulation of endothelial caveolin-1 expression by estrogen, i.e., regulation of caveolin-1 promoter via ERa/ERb interaction with AP-1 and DNA methylation. These studies are of critical importance biologically because they are the first designed specifically for a comprehensive understanding of membrane ER initiated signaling cross-talk with classical nuclear ER via AP-1 to the regulation of eNOS and caveoln-1 gene activation in relation to endothelial NO production by estrogen unique to steroid receptor and endothelial biology. These studies are clinically important as dramatic estrogen biosynthesis and rise in uterine blood flow during pregnancy are essential for the bi-exchange between the mother and fetus and insufficient blood supply causes early embryonic loss, intrauterine growth restriction, preeclampsia, in utero fetal programming of adult diseases and reduced neonatal birthweight, which in turn inversely correlate to perinatal/neonatal morbidity/mortality and cardiovascular well-being of the mother. These studies are relevant to uncover the dilemma of the cardiovascular protective effects of estrogen.
Funding Period: ----------------2001 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi Exogenous nitric oxide stimulates cell proliferation via activation of a mitogen-activated protein kinase pathway in ovine fetoplacental artery endothelial cells
    Jing Zheng
    Department of Obstetrics and Gynecology, Perinatal Research Laboratories, University of Wisconsin, Madison, Wisconsin 53715, USA
    Biol Reprod 74:375-82. 2006
  2. pmc Enhanced cellular responses and distinct gene profiles in human fetoplacental artery endothelial cells under chronic low oxygen
    Yi zhou Jiang
    Department of Obstetrics and Gynecology, University of Wisconsin, Madison, Wisconsin
    Biol Reprod 89:133. 2013
  3. doi Regulation of placental angiogenesis
    Dong Bao Chen
    Department of Obstetrics and Gynecology, University of California, Irvine, California, USA
    Microcirculation 21:15-25. 2014
  4. pmc Human placental microRNAs and preeclampsia
    Dong Bao Chen
    Department of Obstetrics and Gynecology, University of California Irvine, Irvine, CA 92697, USA
    Biol Reprod 88:130. 2013
  5. pmc Transcriptional and functional adaptations of human endothelial cells to physiological chronic low oxygen
    Yi zhou Jiang
    Department of Obstetrics and Gynecology, University of Wisconsin, Madison, Wisconsin
    Biol Reprod 88:114. 2013
  6. pmc Compartmentalizing proximal FGFR1 signaling in ovine placental artery endothelial cell caveolae
    Lin Feng
    Department of Obstetrics and Gynecology, University of California, Irvine, California 92697, USA
    Biol Reprod 87:40. 2012
  7. pmc Distinct roles of HIF1A in endothelial adaptations to physiological and ambient oxygen
    Yi zhou Jiang
    Department of Obstetrics and Gynecology, University of Wisconsin, Madison, WI 53715, United States
    Mol Cell Endocrinol 391:60-7. 2014
  8. pmc Differential activation of multiple signalling pathways dictates eNOS upregulation by FGF2 but not VEGF in placental artery endothelial cells
    Eugenia Mata-Greenwood
    Division of Maternal Fetal Medicine MC0802, Department of Reproductive Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093 0802, USA
    Placenta 29:708-17. 2008
  9. pmc Gender-specific protection of estrogen against gastric acid-induced duodenal injury: stimulation of duodenal mucosal bicarbonate secretion
    Anders Smith
    Department of Medicine, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA
    Endocrinology 149:4554-66. 2008
  10. ncbi Global protein expression profiling underlines reciprocal regulation of caveolin 1 and endothelial nitric oxide synthase expression in ovariectomized sheep uterine artery by estrogen/progesterone replacement therapy
    Dong Bao Chen
    Department of Reproductive Medicine, University of California San Diego, La Jolla, California 92093 0802, USA
    Biol Reprod 74:832-8. 2006

Scientific Experts

  • Cecilia Y Cheung
  • Jayanth Ramadoss
  • Dong Bao Chen
  • Jing Zheng
  • Wu Xiang Liao
  • Lin Feng
  • Hong hai Zhang
  • Eugenia Mata-Greenwood
  • Yi zhou Jiang
  • Wen Wang
  • Kai Wang
  • Yan Li
  • Cai Feng Dai
  • Honghai Zhang
  • K Wang
  • Ronald R Magness
  • Su min Li
  • Christina Kendziorski
  • Ping Wang
  • Louise C Laurent
  • Y Song
  • D B Chen
  • J Zheng
  • Anders Smith
  • Yang Song
  • YunXia Wen
  • Xiao Xian Qian
  • Shi An Huang
  • Jennifer Hodges
  • Seiro Satohisa
  • Sally Agent
  • Mana Parast
  • Stephanie Hachy
  • Yu Ping Wang
  • Jian Guo Geng
  • Jae Yoon Shim
  • Itamar Livnat
  • Jeong Kyu Hoh
  • Ling wen Zeng
  • Deborah A Wing
  • Thomas R Moore
  • R R Magness
  • Y Z Jiang
  • Hui Dong
  • Jimmy Chow
  • Kwang Hyun Ko
  • Cheyanne Contreras
  • Biguang Tuo
  • Xiao Dong
  • Adrian Barker
  • Jason L Austin
  • Steve Jia
  • Adam G King

Detail Information

Publications29

  1. ncbi Exogenous nitric oxide stimulates cell proliferation via activation of a mitogen-activated protein kinase pathway in ovine fetoplacental artery endothelial cells
    Jing Zheng
    Department of Obstetrics and Gynecology, Perinatal Research Laboratories, University of Wisconsin, Madison, Wisconsin 53715, USA
    Biol Reprod 74:375-82. 2006
    ..These data also suggest that SNP could potentially be used to modulate placental angiogenesis...
  2. pmc Enhanced cellular responses and distinct gene profiles in human fetoplacental artery endothelial cells under chronic low oxygen
    Yi zhou Jiang
    Department of Obstetrics and Gynecology, University of Wisconsin, Madison, Wisconsin
    Biol Reprod 89:133. 2013
    ....
  3. doi Regulation of placental angiogenesis
    Dong Bao Chen
    Department of Obstetrics and Gynecology, University of California, Irvine, California, USA
    Microcirculation 21:15-25. 2014
    ....
  4. pmc Human placental microRNAs and preeclampsia
    Dong Bao Chen
    Department of Obstetrics and Gynecology, University of California Irvine, Irvine, CA 92697, USA
    Biol Reprod 88:130. 2013
    ....
  5. pmc Transcriptional and functional adaptations of human endothelial cells to physiological chronic low oxygen
    Yi zhou Jiang
    Department of Obstetrics and Gynecology, University of Wisconsin, Madison, Wisconsin
    Biol Reprod 88:114. 2013
    ..These PCN cells may offer a unique endothelial model, more closely mimicking the in vivo states...
  6. pmc Compartmentalizing proximal FGFR1 signaling in ovine placental artery endothelial cell caveolae
    Lin Feng
    Department of Obstetrics and Gynecology, University of California, Irvine, California 92697, USA
    Biol Reprod 87:40. 2012
    ....
  7. pmc Distinct roles of HIF1A in endothelial adaptations to physiological and ambient oxygen
    Yi zhou Jiang
    Department of Obstetrics and Gynecology, University of Wisconsin, Madison, WI 53715, United States
    Mol Cell Endocrinol 391:60-7. 2014
    ..These data also suggest that HIF1A critically regulates cell proliferation and migration in SCN-, but not in PCN-HUVECs...
  8. pmc Differential activation of multiple signalling pathways dictates eNOS upregulation by FGF2 but not VEGF in placental artery endothelial cells
    Eugenia Mata-Greenwood
    Division of Maternal Fetal Medicine MC0802, Department of Reproductive Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093 0802, USA
    Placenta 29:708-17. 2008
    ..Differences in intensity and temporal patterns of activation of these pathways by FGF2 and VEGF may account for their differential effects on eNOS expression in OFPAE cells...
  9. pmc Gender-specific protection of estrogen against gastric acid-induced duodenal injury: stimulation of duodenal mucosal bicarbonate secretion
    Anders Smith
    Department of Medicine, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA
    Endocrinology 149:4554-66. 2008
    ..Gender-associated differences in basal, acid- and E2-stimulated DMBS may have offered a reasonable explanation for the clinically observed lower incidence of duodenal ulcer in premenopausal women than age-matched men...
  10. ncbi Global protein expression profiling underlines reciprocal regulation of caveolin 1 and endothelial nitric oxide synthase expression in ovariectomized sheep uterine artery by estrogen/progesterone replacement therapy
    Dong Bao Chen
    Department of Reproductive Medicine, University of California San Diego, La Jolla, California 92093 0802, USA
    Biol Reprod 74:832-8. 2006
    ....
  11. pmc Activation of multiple signaling pathways is critical for fibroblast growth factor 2- and vascular endothelial growth factor-stimulated ovine fetoplacental endothelial cell proliferation
    Jing Zheng
    Department of Obstetrics and Gynecology, University of Wisconsin Madison, Perinatal Research Laboratories, PAB1 Meriter Hospital, Madison, WI 53715, USA
    Biol Reprod 78:143-50. 2008
    ....
  12. pmc Transcriptional regulation of endothelial nitric oxide synthase expression in uterine artery endothelial cells by c-Jun/AP-1
    Xiao Xian Qian
    Division of Maternal Fetal Medicine MC0802, Department of Reproductive Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093 0802, USA
    Mol Cell Endocrinol 279:39-51. 2007
    ..Hence, our data show that c-Jun/AP-1 regulates NOS3 transcription involving the proximal AP-1 site in the 5'-regulatory region of the sheep NOS3 gene...
  13. pmc Racial differences in nitric oxide-dependent vasorelaxation
    Eugenia Mata-Greenwood
    Department of Reproductive Medicine, University of California, San Diego, USA
    Reprod Sci 15:9-25. 2008
    ..The major hypotheses postulated on the biological basis of these differences are also highlighted...
  14. pmc Protein phosphatase 3 differentially modulates vascular endothelial growth factor- and fibroblast growth factor 2-stimulated cell proliferation and signaling in ovine fetoplacental artery endothelial cells
    Kai Wang
    Department of Obstetrics and Gynecology, University of Wisconsin, Madison, Wisconsin 53715, USA
    Biol Reprod 79:704-10. 2008
    ..These data also suggest that signaling molecules other than MAPK3/1 and AKT1 play an important role in VEGF- and FGF2-stimulated cell proliferation after knockdown of PPP3CA in OFPAE cells...
  15. pmc Human placental expression of SLIT/ROBO signaling cues: effects of preeclampsia and hypoxia
    Wu Xiang Liao
    Department of Obstetrics and Gynecology, University of California Irvine, Irvine, California 92697, USA
    Biol Reprod 86:111. 2012
    ..Differential expression of SLITs and ROBOs in healthy term and preeclamptic placentas and hypoxia regulation of their expressions in placental cells implicate a potential pathophysiological role for this system in preeclampsia...
  16. pmc Preeclampsia up-regulates angiogenesis-associated microRNA (i.e., miR-17, -20a, and -20b) that target ephrin-B2 and EPHB4 in human placenta
    Wen Wang
    Department of Obstetrics and Gynecology, University of California Irvine, Irvine, California 92697, USA
    J Clin Endocrinol Metab 97:E1051-9. 2012
    ..MicroRNA (miRNA) are a class of noncoding 21- to 25-nucleotide RNA that negatively regulate gene expression posttranscriptionly...
  17. pmc Endothelial caveolar hub regulation of adenosine triphosphate-induced endothelial nitric oxide synthase subcellular partitioning and domain-specific phosphorylation
    Jayanth Ramadoss
    Department of Obstetrics and Gynecology, University of Wisconsin Madison, Madison, WI 53715, USA
    Hypertension 59:1052-9. 2012
    ..Furthermore, these subcellular domain-specific phosphorylation/dephosphorylation events provide evidence relating to eNOS spatio-temporal dynamics...
  18. pmc Compartmentalizing VEGF-induced ERK2/1 signaling in placental artery endothelial cell caveolae: a paradoxical role of caveolin-1 in placental angiogenesis in vitro
    Wu Xiang Liao
    Department of Reproductive Medicine, University of California, San Diego, La Jolla, California 92093, USA
    Mol Endocrinol 23:1428-44. 2009
    ....
  19. pmc Estrogen-responsive nitroso-proteome in uterine artery endothelial cells: role of endothelial nitric oxide synthase and estrogen receptor-β
    Hong hai Zhang
    Department of Obstetrics and Gynecology, University of California Irvine, Irvine, California 92697, USA
    J Cell Physiol 227:146-59. 2012
    ....
  20. pmc Analysis of nitroso-proteomes in normotensive and severe preeclamptic human placentas
    Hong hai Zhang
    Department of Obstetrics and Gynecology, University of California Irvine, CA, USA
    Biol Reprod 84:966-75. 2011
    ..The significantly altered placental nitroso-proteome in preeclampsia suggests that SNO plays a role in the placental pathophysiology in preeclampsia...
  21. pmc Suppression of protein phosphatase 2 differentially modulates VEGF- and FGF2-induced signaling in ovine fetoplacental artery endothelial cells
    Y Song
    Department of Obstetrics and Gynecology, Perinatal Research Laboratories, University of Wisconsin, Madison, WI 53715, USA
    Placenta 30:907-13. 2009
    ..These data also suggest that signaling molecules other than ERK1/2, AKT1, and p38 MAPK are important mediators for VEGF- and FGF2-stimulated OFPAE cell proliferation after PPP2CA suppression...
  22. pmc Hypoxia enhances FGF2- and VEGF-stimulated human placental artery endothelial cell proliferation: roles of MEK1/2/ERK1/2 and PI3K/AKT1 pathways
    K Wang
    Department of Obstetrics and Gynecology, Perinatal Research Laboratories, University of Wisconsin, Madison, WI 53715, USA
    Placenta 30:1045-51. 2009
    ..These results also indicate that hypoxia promotes FGF2- and VEGF-stimulated cell proliferation without further activation of the PI3K/AKT1 and MEK1/2/ERK1/2, respectively...
  23. pmc High-throughput caveolar proteomic signature profile for maternal binge alcohol consumption
    Jayanth Ramadoss
    Department of Obstetrics and Gynecology, Perinatal Research Laboratories, University of Wisconsin, Atrium B Meriter Hospital, 202 South Park Street Madison, WI 53715, USA
    Alcohol 44:691-7. 2010
    ..These data demonstrate that the caveolar proteomic signature created by alcohol shows a promising direction for early detection of FASD...
  24. pmc Activation of AP-1 transcription factors differentiates FGF2 and vascular endothelial growth factor regulation of endothelial nitric-oxide synthase expression in placental artery endothelial cells
    Eugenia Mata-Greenwood
    Department of Reproductive Medicine, University of California San Diego, La Jolla, California 92093, USA
    J Biol Chem 285:17348-58. 2010
    ..Thus, FGF2 induction of NOS3 expression is mainly mediated by AP-1-dependent transcription involving JunB and Fra1 up-regulation via sustained ERK2/1 activation in endothelial cells...
  25. pmc Deciphering mechanisms controlling placental artery endothelial cell migration stimulated by vascular endothelial growth factor
    Wu Xiang Liao
    Department of Obstetrics and Gynecology, University of California Irvine, Orange, CA 92673, USA
    Endocrinology 151:3432-44. 2010
    ..Thus, VEGF-induced placental endothelial cell migration requires activation of complex pathways that are paradoxically regulated by caveolin-1...
  26. ncbi Perspectives of SLIT/ROBO signaling in placental angiogenesis
    Wu Xiang Liao
    Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of California Irvine, Irvine, CA 92697, USA
    Histol Histopathol 25:1181-90. 2010
    ..We also speculate a possible role of this system in pathophysiological placental angiogenesis...
  27. pmc Regulation of caveolin-1 expression and phosphorylation by VEGF in ovine amnion cells
    Cecilia Y Cheung
    Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR 97201, USA
    Reprod Sci 17:1112-9. 2010
    ..Our observations support the hypothesis that VEGF regulates amniotic fluid transport across the amnion by stimulating caveolin-1 activity to mediate caveolar function in amnion cells...
  28. pmc Rac1-dependent intracellular superoxide formation mediates vascular endothelial growth factor-induced placental angiogenesis in vitro
    Su min Li
    Department of Reproductive Medicine, University of California San Diego, La Jolla, California 92093, USA
    Endocrinology 151:5315-25. 2010
    ..This NADPH oxidase system appears to generate the second messenger superoxide that plays a critical role in the signaling control of the VEGF-induced placental angiogenesis...
  29. pmc Estradiol-17beta stimulates specific receptor and endogenous nitric oxide-dependent dynamic endothelial protein S-nitrosylation: analysis of endothelial nitrosyl-proteome
    Hong hai Zhang
    Department of Obstetrics and Gynecology, University of California Irvine, Irvine, California 92697, USA
    Endocrinology 151:3874-87. 2010
    ..These findings signify a critical next step for the understanding of the biological targets of enhanced NO production by estrogens...