Thrombin activation of endometrial endothelial cells: a possible role in intrauterine growth restriction
Abstract
Preeclampsia (PE), intrauterine growth restriction (IUGR) and abruption with or without fetal loss are associated with reduced uteroplacental blood flow, decidual vasculopathy, endothelial cell dysfunction, thrombosis, inflammation and hemorrhage. Our hypothesis is that reduced uteroplacental blood flow causes focal decidual hypoxia that generates vascular endothelial growth factor (VEGF). The latter acts directly on decidual endothelial cells to induce aberrant expression of tissue factor (TF), the primary initiator of coagulation. This in turn generates thrombin that induces: i) further TF expression; and ii) inflammatory cytokines. Both VEGF and TF induce aberrant angiogenesis-vessel maintenance reflected by endothelial cell fenestrations and induction of a prothrombotic surface causing both the decidual hemorrhage (i.e. abruption) and thrombosis (i.e. uteroplacental vascular insufficiency) observed in these adverse pregnancy outcomes. This novel hypothesis is supported by our finding of TF expression in decidual endothelium of pregnancies complicated by IUGR and/or fetal loss. Moreover, treatment of cultured endometrial endothelial cells with VEGF or thrombin induces TF protein and mRNA expression. Quantitative RT-PCR analysis indicates that thrombin enhances (>10-fold) the output of diverse inflammatory cytokines in these cultures. The greatest effect (>2-log) was seen on macrophage inflammatory protein 3alpha (MIP3alpha). In vitro, thrombin results in endometrial endothelial cell aggregations and changes in the apoptotic pathway. Thus, we postulate that reductions in uteroplacental flow initiate a cascade of molecular effects leading to hypoxia, thrombosis, inflammation, and endothelial cell dysfunction resulting in untoward pregnancy outcomes.
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Higher levels of vascular endothelial growth factor stimulate decidual endothelial cells to generate more tissue factor and more thrombin.
“Higher levels of vascular endothelial growth factor stimulate decidual endothelial cells to generate more tissue factor and more thrombin (11).”
From Placental abruption at near-term and term gestations: Pathophysiology, epidemiology, diagnosis, and management (2023) · cites this paper as [11]
Relative hypoxia promotes expression of vascular endothelial growth factor, which may alter the inflammatory response to decidual bleeding.
“The relative hypoxia also promotes expression of vascular endothelial growth factor, which may alter the inflammatory response to decidual bleeding (11).”
From Placental abruption at near-term and term gestations: Pathophysiology, epidemiology, diagnosis, and management (2023) · cites this paper as [11]
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- Authors
- Huang, S.-T., Schatz, F., Salafia, C., Stocco, C., Lockwood, C., & Krikun, G.
- Affiliations
- Yale University (US)
- Columbia University (US)
- Corresponding author
- Krikun, Graciela
- Venue
- Thrombosis and Haemostasis
- Publisher
- Georg Thieme Verlag KG
- Published
- 2007
- Volume
- 97
- Issue
- 02
- Pages
- 245-253
- ISSN
- 0340-6245 (ISSN-L)
- 2567-689X
- OpenAlex
- W2093238013
- Cited by
- 49
- References
- 0
- Citations by year
- 2025: 4 · 2024: 1 · 2023: 4 · 2022: 4 · 2021: 2 · 2020: 4 · 2019: 4 · 2018: 1 · 2017: 2 · 2016: 3 · 2015: 2 · 2014: 1 · 2013: 3 · 2012: 2
- FWCI
- 3.89
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Thrombosis and Haemostasis (publishedVersion)
- PubMed (publishedVersion)
- Funders
- NIH
- Topics
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Keywords
- thrombin, endometrial endothelial cells, fetal growth restriction, preeclampsia, placental abruption, tissue factor, vascular endothelial growth factor, uteroplacental blood flow, inflammatory cytokines, macrophage inflammatory protein-3α, endothelial cell apoptosis, endothelial dysfunction, pregnancy complications
- MeSH terms
- Cell Aggregation, Cells, Cultured, Decidua, Endometrium, Female, Fetal Growth Retardation, Gene Expression Regulation, Gestational Age, Humans, Pregnancy, Pregnancy Complications, RNA, Messenger, Thrombin, Thromboplastin, Time Factors, Cytokines, NF-kappa B, Placental Circulation, Vascular Endothelial Growth Factor A, Angiogenic Proteins, Endothelial Cells, Apoptosis Regulatory Proteins
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