CoChat
Sign Up
Cited by 377Pregnancy and preeclampsia studiesReproductive System and PregnancyPreterm Birth and Chorioamnionitis

Oxygen and Placental Development During the First Trimester: Implications for the Pathophysiology of Pre-eclampsia

Caniggia, I., Winter, J., Lye, S.J., Post, M.·2000·Placenta
DOI 10.1053/plac.1999.0522
Open this paper in CoChat — free account

Abstract

During early pregnancy, placentation occurs in a relatively hypoxic environment which is essential for appropriate embryonic development. Intervillous blood flow increases at around 10-12 weeks of gestation and results in exposure of the trophoblast to increased oxygen tension (PO2). Prior to this time, low oxygen appears to prevent trophoblast differentiation towards an invasive phenotype. In other mammalian systems, oxygen tension effects are mediated by hypoxia inducible factor-1 (HIF-1). We found that the ontogeny of HIF-1alpha subunit expression during the first trimester of gestation parallels that of transforming growth factor-beta3 (TGFbeta3), an inhibitor of early trophoblast differentiation. Expression of both molecules is high in early pregnancy and falls at around 10 weeks of gestation when placental PO2 levels are believed to increase. Antisense-induced inhibition of HIF-1alpha inhibited the expression of TGFbeta3, and stimulated extravillous trophoblast (EVT) outgrowth and invasion. Of clinical significance we found that TGFbeta3 expression was increased in pre-eclamptic placentae when compared to age-matched controls. Significantly, inhibition of TGFbeta3 by antisense oligonucleotides or antibodies restored the invasive capability to the trophoblast cells in pre-eclamptic explants. We speculate that if oxygen tension fails to increase, or trophoblasts do not detect this increase, HIF-1alpha and TGFbeta3 expression remain high, resulting in shallow trophoblast invasion and predisposing the pregnancy to pre-eclampsia. Effective fetal-maternal interactions during early placentation are critical for a successful pregnancy. Optimal placental perfusion requires the controlled invasion of trophoblast cells deep into the decidua to the spiral arteries. Trophoblast stem cells, also referred to as cytotrophoblast cells, reside in chorionic villi of two types, floating and anchoring villi. Floating villi, which represent the vast majority of chorionic villi, are bathed in maternal blood and primarily perform gas and nutrient exchange for the developing embryo. During early placentation, cytotrophoblast cells in the floating villi proliferate and differentiate by fusing to form the multinucleate syncytiotrophoblast layer. Cytotrophoblast cells in anchoring villi either fuse to form the syncytiotrophoblast layer, or break through the syncytium at selected sites and form multilayered columns of non-polarized extravillous trophoblast cells, which physically connect the embryo to the uterine wall (Figure 1). The extravillous trophoblast cells invade into the uterine wall as far as the first third of the myometrium and its associated spiral arteries, where they disrupt the endothelium and the smooth muscle layer and replace the vascular wall. This results in the conversion of the narrow calibre arteries into distended uteroplacental arteries, thereby increasing blood flow to the placenta and allowing an adequate supply of oxygen and nutrients to the growing fetus. The invasive activity of the extravillous trophoblast cells is at a maximum during the first trimester of gestation, peaking at around 10-12 weeks and declining thereafter. Insufficient invasion contributes to the development of pre-eclampsia, which often results in fetal intrauterine growth restriction, maternal hypertension and proteinuria. In contrast, unrestricted invasion is associated with premalignant conditions, such as invasive mole, and with malignant choriocarcinoma. Invading trophoblast cells undergo striking and rapid changes in cellular functions that are temporally and spatially regulated along the invasive pathway (Figure 1) (Cross, Werb and Fisher, 1994. The formation of the anchoring villi is accompanied by changes in synthesis and degradation of extracellular matrix proteins and their receptors, and changes in the spatial distribution of extracellular matrix proteins, as well as changes in the expression of adhesion molecules (Damsky, Fitzgerald and

Integrity signals

Registry

Crossref · 10.1053/plac.1999.0522

Cites

20 of 20 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Aberrant HIF signaling has been implicated in the pathophysiology of pre-eclampsia, in particular the early-onset form when the PHDs do not appear to sense oxygen, and may be responsible for abnormal placental secretion of angiogenic regulatory factors.

    “Aberrant HIF signaling has been implicated in the pathophysiology of pre-eclampsia, in particular of the early-onset form when the PHDs do not appear to sense oxygen (90, 448, 467), and may be responsible for the abnormal placental secretion of angiogenic regulatory factors that is thought to precipitate the clinical syndrome (413).”

    From Placental Origins of Chronic Disease (2016) · cites this paper as [90]

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Caniggia, I., Winter, J., Lye, S. J., & Post, M.
Affiliations
Mount Sinai Hospital (CA)
ORCID
Venue
Placenta
Publisher
Elsevier BV
Published
2000-03
Volume
21
Pages
S25-S30
ISSN
0143-4004 (ISSN-L)
DOI
10.1053/plac.1999.0522
OpenAlex
W2081871156
Cited by
377
References
20
Citations by year
2026: 5 · 2025: 10 · 2024: 14 · 2023: 13 · 2022: 12 · 2021: 13 · 2020: 8 · 2019: 16 · 2018: 24 · 2017: 15 · 2016: 19 · 2015: 10 · 2014: 21 · 2013: 19 · 2012: 24
FWCI
14.78
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Placenta (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
  • Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
  • Health Sciences › Medicine › Epidemiology › Preterm Birth and Chorioamnionitis
Keywords
preeclampsia, placental development, first trimester, trophoblast invasion, extravillous trophoblast, oxygen partial pressure, hypoxia-inducible factor-1α, transforming growth factor-beta3, placental hypoxia, syncytiotrophoblast, placental perfusion, spiral arteries, trophoblast stem cells, antisense oligonucleotides
MeSH terms
DNA-Binding Proteins, Female, Humans, Nuclear Proteins, Oxygen, Placentation, Pre-Eclampsia, Pregnancy, Pregnancy Trimester, First, RNA, Messenger, Transcription Factors, Transforming Growth Factor beta, Oligonucleotides, Antisense, In Situ Hybridization, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit, In Vitro Techniques

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review