Placenta
Volume 30, Issue 12 , Pages 1045-1051, December 2009

Hypoxia Enhances FGF2- and VEGF-Stimulated Human Placental Artery Endothelial Cell Proliferation: Roles of MEK1/2/ERK1/2 and PI3K/AKT1 Pathways☆

  • K. Wang

      Affiliations

    • Department of Obstetrics and Gynecology, Perinatal Research Laboratories, University of Wisconsin, Madison, WI 53715, USA
    • ,
  • Y.-z. Jiang

      Affiliations

    • Department of Obstetrics and Gynecology, Perinatal Research Laboratories, University of Wisconsin, Madison, WI 53715, USA
    • ,
  • D.-b. Chen

      Affiliations

    • Department of Obstetrics and Gynecology, University of California, Irvine, CA 92697, USA
    • ,
  • J. Zheng

      Affiliations

    • Department of Obstetrics and Gynecology, Perinatal Research Laboratories, University of Wisconsin, Madison, WI 53715, USA
    • Corresponding Author InformationCorresponding author at: Department of Obstetrics and Gynecology, University of Wisconsin, PAB1, Meriter Hospital, 202 S. Park St., Madison, WI 53715. Tel.: +1 608 417 6314; fax:+1 608 257 1304.

Accepted 15 October 2009. published online 06 November 2009.

Abstract 

Placental development occurs under a low oxygen (2–8% O2) environment, which is critical for placental development and angiogenesis. In this study, we examined if hypoxia affected fibroblast growth factor-2 (FGF2)- and vascular endothelial growth factor (VEGF)-stimulated cell proliferation via the mitogen-activated protein kinase kinase 1/2 (MEK1/2)/extracellular signal-regulated kinases 1/2 (ERK1/2) and phosphatidylinositol-3 kinase (PI3K)/v-akt murine thymomaviral oncogene homologue (AKT1) pathways in human placental artery endothelial (HPAE) cells. We observed that under normoxia (∼20% O2), FGF2 and VEGF dose-dependently stimulated cell proliferation. Hypoxia (3% O2) significantly promoted FGF2- and VEGF-stimulated cell proliferation as compared to normoxia. Under both normoxia and hypoxia, FGF2 rapidly induced ERK1/2 and AKT1 phosphorylation, while VEGF-induced ERK1/2, but not AKT1 phosphorylation. However, hypoxia did not significantly alter FGF2- and VEGF-induced ERK1/2 and AKT1 phosphorylation as compared to normoxia. PD98059 (a MEK1/2 inhibitor) at 20μM and LY294002 (a PI3K inhibitor) at 5μM attenuated FGF2- and VEGF-induced phosphorylation of ERK1/2 and AKT1, respectively. PD98059, even at doses that drastically inhibited FGF2-induced ERK1/2 phosphorylation (20μM) and caused cell loss (40μM), did not affect FGF2-stimulated cell proliferation, which was confirmed by U0126 (another potent MEK1/2 inhibitor). PD98059, however, dose-dependently inhibited VEGF-stimulated cell proliferation. Conversely, LY294002 dose-dependently inhibited FGF2-, but not VEGF-stimulated cell proliferation. These data suggest that in the MEK1/2/ERK1/2 and PI3K/AKT1 pathways differentially mediate FGF2- and VEGF-stimulated HPAE cell proliferation. 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.

Keywords: Hypoxia, Placenta, Endothelial cells, Kinases, Angiogenesis

To access this article, please choose from the options below

Login to an existing account or Register a new account.

  • Purchase this article for 31.50 USD (You must login/register to purchase this article)

    Online access for 24 hours. The PDF version can be downloaded as your permanent record.

  • Subscribe to this title

    Get unlimited online access to this article and all other articles in this title 24/7 for one year.

  • Claim access now

    For current subscribers with Society Membership or Account Number.

  • Visit SciVerse ScienceDirect to see if you have access via your institution.
 

☆ This work was supported in part by the National Institutes of Health grants HL64703 and HD38843 (JZ) and HL74947 & HL70562 (DBC).

PII: S0143-4004(09)00330-0

doi:10.1016/j.placenta.2009.10.007

Placenta
Volume 30, Issue 12 , Pages 1045-1051, December 2009

Article Tools

* Image Usage & Resolution