The long-term goals of this applicant are to determine the cellular & molecular mechanisms mediating placental angiogenesis & ultimately control placental blood flow and function. We will use Ovine Fetal Placental Artery Endothelial (OFPAE) & Human Placental Microvascular (HPME) cell lines for this purpose. These placental endothelial cells were chosen because dramatic placental vascular growth during human & ovine pregnancy is associated with dramatic increases in umbilical blood flow, which is critical for fetal growth & survival as well as neonatal birth weights and survivability. The angiogenic factors, bFGF & VEGF, are key factors regulating angiogenesis & production of endothelial nitric oxide (NO; a potent vasodilator). Actions of bFGF & VEGF are tightly mediated by proteins kinases (i.e. Akt & p38 MAPK) & protein phosphatases (i.e. PP2A & PP2B). The hypothesis is that in the placenta bFGF- & VEGF-induced angiogenesis is modulated in part via activation of the PI3K/Akt and p38 MAPK signal pathways as well as inhibition of PP2A and PP2B, which in turn increase NO production, so promoting fetal placental angiogenesis.
3 Specific Aims will be addressed using the well-characterized OFPAE cell line. We will determine:
AIM I. if bFGF- & VEGF-stimulated cell proliferation & migration are mediated in part via activation of the PI3K/Akt & p38 MAPK pathways by treating cells with bFGF or VEGF in the presence of specific PI3K or p38 MAPK inhibitors, using cell proliferation & migration assays, Western analysis, and kinase activity assays;
AIM II. if bFGF & VEGF activate Akt & p38 MAPK in part via inhibiting PP2A & PP2B activities, by treating cells with bFGF or VEGF in the presence of the specific protein phosphatase inhibitors, using Western analysis, protein phosphatase & kinase activity assays, and cell proliferation & migration assays;
and AIM III. If bFGF- & VEGF elevate NO production via activation of PI3K/Akt & p38 MAPK as well as inhibition of PP2A & PP2B, regulating eNOS phosphorylation. An additional Specific Aim IV will use the HPME cell line to confirm the key observations made from OFPAE cells. These studies will glean important information on the mechanisms regulating placental angiogenesis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL064703-08
Application #
7470610
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Pemberton, Victoria
Project Start
2000-09-01
Project End
2010-05-31
Budget Start
2008-06-01
Budget End
2010-05-31
Support Year
8
Fiscal Year
2008
Total Cost
$241,431
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
Chen, Dong-Bao; Zheng, Jing (2014) Regulation of placental angiogenesis. Microcirculation 21:15-25
Jiang, Yi-Zhou; Wang, Kai; Li, Yan et al. (2013) Transcriptional and functional adaptations of human endothelial cells to physiological chronic low oxygen. Biol Reprod 88:114
Wang, Kai; Zheng, Jing (2012) Signaling regulation of fetoplacental angiogenesis. J Endocrinol 212:243-55
Feng, Lin; Liao, Wu-Xiang; Luo, Quan et al. (2012) Caveolin-1 orchestrates fibroblast growth factor 2 signaling control of angiogenesis in placental artery endothelial cell caveolae. J Cell Physiol 227:2480-91
Dai, Cai Feng; Jiang, Yi Zhou; Li, Yan et al. (2011) Expression and roles of Slit/Robo in human ovarian cancer. Histochem Cell Biol 135:475-85
Jobe, Sheikh O; Ramadoss, Jayanth; Koch, Jill M et al. (2010) Estradiol-17beta and its cytochrome P450- and catechol-O-methyltransferase-derived metabolites stimulate proliferation in uterine artery endothelial cells: role of estrogen receptor-alpha versus estrogen receptor-beta. Hypertension 55:1005-11
Mata-Greenwood, Eugenia; Liao, Wu-xiang; Wang, Wen et al. (2010) 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. J Biol Chem 285:17348-58
Liao, Wu-xiang; Feng, Lin; Zheng, Jing et al. (2010) Deciphering mechanisms controlling placental artery endothelial cell migration stimulated by vascular endothelial growth factor. Endocrinology 151:3432-44
Jiang, Yi-zhou; Wang, Kai; Fang, Roy et al. (2010) Expression of aryl hydrocarbon receptor in human placentas and fetal tissues. J Histochem Cytochem 58:679-85
Liao, Wu-Xiang; Feng, Lin; Zhang, Honghai et al. (2009) Compartmentalizing VEGF-induced ERK2/1 signaling in placental artery endothelial cell caveolae: a paradoxical role of caveolin-1 in placental angiogenesis in vitro. Mol Endocrinol 23:1428-44

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