PMID- 10712429
OWN - NLM
STAT- MEDLINE
DCOM- 20000330
LR  - 20240410
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 105
IP  - 5
DP  - 2000 Mar
TI  - Hypoxia-inducible factor-1 mediates the biological effects of oxygen on human 
      trophoblast differentiation through TGFbeta(3).
PG  - 577-87
AB  - During early pregnancy, placentation occurs in a relatively hypoxic environment 
      that is essential for appropriate embryonic development. Intervillous blood flow 
      increases around 10 to 12 weeks of gestation and results in exposure of 
      trophoblast cells to increased oxygen tension. Before this time, low oxygen 
      appears to prevent trophoblast differentiation toward an invasive phenotype. 
      Using human villous explants of 5-8 weeks' gestation, we found that low oxygen 
      tension triggered trophoblast proliferation, fibronectin synthesis, alpha(5) 
      integrin expression, and gelatinase A activity. These biochemical markers were 
      barely detectable under oxic conditions. We therefore examined the placental 
      expression of hypoxia-inducible factor-1 (HIF-1), a master regulator of oxygen 
      homeostasis, and determined that expression of HIF-1alpha subunit during the 
      first trimester of gestation parallels that of TGFbeta(3), an inhibitor of 
      extravillous trophoblast differentiation. Expression of both molecules is high in 
      early pregnancy and falls around 9 weeks of gestation, when placental pO(2) 
      levels are believed to increase. Increasing oxygen tension induced a similar 
      decrease in expression in cultured explants. Moreover, antisense inhibition of 
      HIF-1alpha expression in hypoxic explants inhibited expression of TGFbeta(3), 
      arrested cell proliferation, decreased alpha(5) expression and gelatinase A 
      activity, and triggered biochemical markers of an invasive trophoblast phenotype 
      such as alpha(1) integrin and gelatinase B expression. These data suggest that 
      the oxygen-regulated early events of trophoblast differentiation are in part 
      mediated by TGFbeta(3) through HIF-1 transcription factors.
FAU - Caniggia, I
AU  - Caniggia I
AD  - Department of Pediatrics, The Hospital for Sick Children Research Institute, 
      Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. 
      Caniggia@mshri.on.ca
FAU - Mostachfi, H
AU  - Mostachfi H
FAU - Winter, J
AU  - Winter J
FAU - Gassmann, M
AU  - Gassmann M
FAU - Lye, S J
AU  - Lye SJ
FAU - Kuliszewski, M
AU  - Kuliszewski M
FAU - Post, M
AU  - Post M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Fibronectins)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Oligonucleotides, Antisense)
RN  - 0 (RNA, Messenger)
RN  - 0 (Transcription Factors)
RN  - 0 (Transforming Growth Factor beta)
RN  - EC 3.4.24.- (Gelatinases)
RN  - S88TT14065 (Oxygen)
SB  - IM
CIN - J Clin Invest. 2000 Mar;105(5):559-60. PMID: 10712424
MH  - Cell Differentiation
MH  - Culture Techniques
MH  - DNA-Binding Proteins/biosynthesis/*metabolism
MH  - Female
MH  - Fibronectins/metabolism
MH  - Gelatinases/metabolism
MH  - Gene Expression Regulation
MH  - Gestational Age
MH  - Humans
MH  - Hypoxia/metabolism
MH  - Hypoxia-Inducible Factor 1
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - Immunohistochemistry
MH  - In Situ Hybridization
MH  - Nuclear Proteins/biosynthesis/*metabolism
MH  - Oligonucleotides, Antisense/pharmacology
MH  - Oxygen/*physiology
MH  - Placenta/*physiology
MH  - Pregnancy
MH  - RNA, Messenger/metabolism
MH  - *Transcription Factors
MH  - Transforming Growth Factor beta/biosynthesis/genetics/*metabolism
MH  - Trophoblasts/metabolism/*physiology
PMC - PMC289179
EDAT- 2000/03/11 09:00
MHDA- 2000/04/01 09:00
PMCR- 2000/03/01
CRDT- 2000/03/11 09:00
PHST- 2000/03/11 09:00 [pubmed]
PHST- 2000/04/01 09:00 [medline]
PHST- 2000/03/11 09:00 [entrez]
PHST- 2000/03/01 00:00 [pmc-release]
AID - 08316 [pii]
AID - 10.1172/JCI8316 [doi]
PST - ppublish
SO  - J Clin Invest. 2000 Mar;105(5):577-87. doi: 10.1172/JCI8316.