Enhanced HIF2α expression during human trophoblast differentiation into syncytiotrophoblast suppresses transcription of placental growth factor

被引:26
作者
Fujii, Tatsuya [1 ]
Nagamatsu, Takeshi [1 ]
Morita, Kazuki [1 ]
Schust, Danny J. [2 ]
Iriyama, Takayuki [1 ]
Komatsu, Atsushi [1 ]
Osuga, Yutaka [1 ]
Fujii, Tomoyuki [1 ]
机构
[1] Univ Tokyo, Dept Obstet & Gynecol, Fac Med, Tokyo, Japan
[2] Univ Missouri, Dept Obstet Gynecol & Womens Hlth, Columbia, MO USA
来源
SCIENTIFIC REPORTS | 2017年 / 7卷
基金
日本学术振兴会;
关键词
HYPOXIA-INDUCIBLE FACTORS; TYROSINE KINASE-1; HIF; ANGIOGENESIS; OXYGEN; CELLS; HIF-2-ALPHA; ACTIVATION; ROLES; WOMEN;
D O I
10.1038/s41598-017-12685-w
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Placental growth factor (PlGF), abundantly produced from trophoblasts is involved in placental angiogenesis. The regulatory mechanism of its expression is poorly understood. Hypoxia inducible factors (HIFs) are centrally involved in the modulation of cellular function in response to low oxygen conditions. This study aimed to clarify HIF1 alpha and HIF2 alpha expression patterns during cytotrophoblast differentiation into syncytiotrophoblast and the impact of any changes on PlGF expression. HIF proteins were induced remarkably under low oxygen condition (2%). HIF1 alpha expression decreased and HIF2 alpha expression increased when syncytialization of cultured cytotrophoblasts is progressed. Those expression changes of HIF proteins in the process of in-vitro syncytialization was congruent with the immunohistochemical findings in preeclamptic placenta as well as uncomplicated placenta. Low oxygen condition was also associated with reduced PlGF production in syncytializing primary cells and BeWo choriocarcinoma cells. Small interfering RNA-mediated HIF2 alpha knockdown in BeWo cells abrogated hypoxia-associated decreases in PlGF secretion; HIF1 alpha silencing had no significant effect on PlGF secretion. In summary, HIF2 alpha, rather than HIF1a, is most affected by reduced oxygen level during syncytialization and increases in HIF2 alpha trigger a reduction of PlGF production. Our findings suggest new and important connections between HIF proteins and PlGF pathways in the regulation of placental angiogenesis.
引用
收藏
页数:10
相关论文
共 38 条
  • [1] Regulation of placental vascular endothelial growth factor (VEGF) and placenta growth factor (PIGF) and soluble Flt-1 by oxygen - A review
    Ahmed, A
    Dunk, C
    Ahmad, S
    Khaliq, A
    [J]. PLACENTA, 2000, 21 : S16 - S24
  • [2] Maternal plasma soluble fins-like tyrosine kinase-1 and free vascular endothelial growth factor at 11 to 13 weeks of gestation in preeclampsia
    Akolekar, Ranjit
    de Cruz, Jader
    Foidart, Jean-Michel
    Munaut, Carine
    Nicolaides, Kypros H.
    [J]. PRENATAL DIAGNOSIS, 2010, 30 (03) : 191 - 197
  • [3] Placental expression of VEGF family mRNA in adverse pregnancy outcomes
    Andraweera, P. H.
    Dekker, G. A.
    Laurence, J. A.
    Roberts, C. T.
    [J]. PLACENTA, 2012, 33 (06) : 467 - 472
  • [4] Placental Endoplasmic Reticulum Stress and Oxidative Stress in the Pathophysiology of Unexplained Intrauterine Growth Restriction and Early Onset Preeclampsia
    Burton, G. J.
    Yung, H. -W.
    Cindrova-Davies, T.
    Charnock-Jones, D. S.
    [J]. PLACENTA, 2009, 30 : S43 - S48
  • [5] Energy status and HIF signalling in chorionic villi show no evidence of hypoxic stress during human early placental development
    Cindrova-Davies, T.
    van Patot, M. Tissot
    Gardner, L.
    Jauniaux, E.
    Burton, G. J.
    Charnock-Jones, D. S.
    [J]. MOLECULAR HUMAN REPRODUCTION, 2015, 21 (03) : 296 - 308
  • [6] Hypoxia-indulcible factors 1α and 2α regulate trophoblast differentiation
    Dahl, KDC
    Fryer, BH
    Mack, FA
    Compernolle, V
    Maltepe, E
    Adelman, DM
    Carmeliet, P
    Simon, MC
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 2005, 25 (23) : 10479 - 10491
  • [7] Opposing roles for HIF-1α and HIF-2α in the regulation of angiogenesis by mononuclear phagocytes
    Eubank, Tim D.
    Roda, Julie M.
    Liu, Haowen
    O'Neil, Todd
    Marsh, Clay B.
    [J]. BLOOD, 2011, 117 (01) : 323 - 332
  • [8] Why is placentation abnormal in preeclampsia?
    Fisher, Susan J.
    [J]. AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY, 2015, 213 (04) : S115 - S122
  • [9] Regulation of human placental development by oxygen tension
    Genbacev, O
    Zhou, Y
    Ludlow, JW
    Fisher, SJ
    [J]. SCIENCE, 1997, 277 (5332) : 1669 - 1672
  • [10] Defective placental vasculogenesis causes embryonic lethality in VHL-deficient mice
    Gnarra, JR
    Ward, JM
    Porter, FD
    Wagner, JR
    Devor, DE
    Grinberg, A
    EmmertBuck, MR
    Westphal, H
    Klausner, RD
    Linehan, WM
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (17) : 9102 - 9107