Elucidating the Pathogenesis of Pre-eclampsia Using In Vitro Models of Spiral Uterine Artery Remodelling

McNally, Ross; Alqudah, Abdelrahim; Obradović, Danilo; McClements, Lana

doi:10.1007/s11906-017-0786-2

Cited by 50 publications

(49 citation statements)

References 101 publications

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“…A well-known compensatory pro-angiogenic factor activated by hypoxia (34), hypoxia-inducible factor 1α (HIF-1α) was also identified in all three conditions. These findings align with wellestablished knowledge that one of the root causes of preeclampsia is inappropriate implantation and development of the placenta due to poor SUA remodelling (2,35). Hypertension and HFpEF are also characterised by aberrant angiogenesis, vascular remodelling and fibrosis (36,37).…”

Section: Overlapping Pathophysiological Mechanisms Between Preeclampssupporting

confidence: 88%

“…Preeclampsia is a multifactorial condition with molecular regulation of its pathogenesis remaining poorly understood. However, the development of preeclampsia has been closely associated with abnormal placentation occurring in the early stages of pregnancy where impaired spiral uterine artery (SUA) remodelling plays a significant role (2). The lack of the SUA remodelling represents an initial step leading to vascular changes and hypertension (3).…”

Section: Introductionmentioning

confidence: 99%

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Overlapping Pathogenic Signalling Pathways and Biomarkers in Preeclampsia and Cardiovascular Disease

Šuvakov

Bonner

Nikolić

et al. 2020

Preprint

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Corresponding authorsHighlights  Women with preeclampsia have increased risk of cardiovascular disease later in life but the mechanism is poorly understood. "In silico" analyses of publically available datasets provided overlapping biomarkers and pathogenic pathways between preeclampsia, hypertension and heart failure with preserved ejection fraction (HFpEF). These data could be utilised in the future studies that may lead to the development of better risk stratification strategies or preventative treatments for women post preeclampsia. AbstractObjectives: Preeclampsia is a cardiovascular pregnancy complication which occurs in 5-10% of pregnancies that can lead to a number of pregnancy complications including maternal and foetal death. Long-term, preeclampsia is associated with up to 8-fold increased risk of cardiovascular disease (CVD) for both mothers and their offspring. The lack of mechanistic data in relation to the causes or consequences of preeclampsia has prevented the development of effective therapeutic or monitoring strategies. Study design:This study investigates common underlying mechanisms of preeclampsia and CVD, specifically hypertension and heart failure with preserved ejection fraction (HFpEF)using "in silico" approach of publicly available datasets. Integrated techniques were designed to mine data repositories and identify relevant biomarkers associated with these three conditions. Main outcomes measures:The knowledge base tools were employed that enabled the analysis of these biomarkers to discover potential molecular and biological links between these three conditions.Results: Our bioinformatics "in silico" analyses of the publically available datasets identified 76 common biomarkers between preeclampsia, hypertension and HFpEF. These biomarkers were representative of 29 pathways commonly enriched across the three conditions which were largely related to inflammation, metabolism, angiogenesis, remodelling, haemostasis, apoptosis, endoplasmic reticulum (ER) stress signalling and the renin-angiotensin-aldosterone (RAAS) system. Conclusions:This bioinformatics approach which uses the wealth of scientific data available in public repositories can be helpful to gain a deeper understanding of the overlapping pathogenic mechanisms of associated diseases, which could be explored as biomarkers or targets to prevent long-term cardiovascular complications such as hypertension and HFpEF following preeclampsia. Abstract word count: 244 wordsMain text word count: 2580 words Total word count: 4653 words

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Section: Overlapping Pathophysiological Mechanisms Between Preeclampssupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Overlapping Pathogenic Signalling Pathways and Biomarkers in Preeclampsia and Cardiovascular Disease

Šuvakov

Bonner

Nikolić

et al. 2020

Preprint

Self Cite

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“…According to the latest published articles, the proliferation, invasion and migration of trophoblast cells into the uterus serve important roles in human placenta formation and embryo implantation (5,6). decreased invasive ability, and increased apoptosis, of trophoblast cells are two major causes of PE during the critical stage of placental implantation (7). Once certain changes in the regulatory factors have taken place, trophoblast cells will greatly proliferate and develop into choriocarcinoma, which causes damage to the tissues and blood vessels surrounding the uterus, and distant metastasis at an early stage.…”

Section: Introductionmentioning

confidence: 99%

LRP6 is involved in the proliferation, migration and invasion of trophoblast cells via miR‑346

Zhang

et al. 2020

Int J Mol Med

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Low-density lipoprotein receptor-related protein 6 (LRP6) promotes metastasis in numerous types of cancer; however, its role in trophoblast cells has been less frequently reported. In the present study, the effects of up-and downregulation of LRP6 on trophoblast cells were investigated accordingly. The study aimed to develop a therapeutic target for gestational choriocarcinoma. The expression levels of LRP6 in pre-eclampsia (PE) tissues, trophoblast cell lines and gestational choriocarcinoma cells were determined using reverse transcription-quantitative polymerase chain reaction (RT-qPcR) assay. double-luciferase reporter analysis was conducted to detect the regulatory gene of LRP6. Furthermore, the proliferative, migratory and invasive abilities of trophoblasts and gestational choriocarcinoma cells were determined by ccK-8, wound healing, and Transwell assays, respectively. The expression levels of the genes and proteins of interest [matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), and TIMP-2] associated with tumor cell invasion were measured by performing RT-qPcR and western blotting, respectively. The National center for Biotechnology Information database revealed that LRP6 was relatively highly expressed in placental tissues, but was poorly expressed in PE tissues and trophoblast cell lines. The upregulation of LRP6 not only increased the activity, migration and invasion of trophoblast cells, but it also promoted the expression of MMP-2 and MMP-9, whereas it inhibited the expression levels of TIMP-1 and TIMP-2. Such results followed the opposite trend to those of downregulation of LRP6 in gestational choriocarcinoma cells. Moreover, LRP6 was predicted to be the target gene for microRNA (miR)-346, which was highly expressed in PE tissues and trophoblast cell lines. The present study also revealed that LRP6 could reverse the effects of miR-346 on the proliferation, migration and invasion of trophoblast cells. Therefore, considered collectively, the results of the present study have demonstrated that LRP6 is involved in the proliferation, migration and invasion of trophoblast cells via miR-346, and that LRP6 may serve as a potential target in cancer treatment.

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“…[10][11][12] To date, no miRNAs have been implicated in the specific process of enEVT differentiation and spiral artery remodeling. 13 miR-218-5p is processed from two precursor genes, MIR218-1 and MIR218-2, located in introns of SLIT2 and SLIT3, respectively. The Slit-Robo pathway is well known for its role in neuronal and vascular development.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-218-5p Promotes Endovascular Trophoblast Differentiation and Spiral Artery Remodeling

et al. 2018

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Preeclampsia (PE) is the leading cause of maternal and neonatal morbidity and mortality. Defects in trophoblast invasion, differentiation of endovascular extravillous trophoblasts (enEVTs), and spiral artery remodeling are key factors in PE development. There are no markers clinically available to predict PE, leaving expedited delivery as the only effective therapy. Dysregulation of miRNA in clinical tissues and maternal circulation have opened a new avenue for biomarker discovery. In this study, we investigated the role of miR-218-5p in PE development. miR-218-5p was highly expressed in EVTs and significantly downregulated in PE placentas. Using first-trimester trophoblast cell lines and human placental explants, we found that miR-218-5p overexpression promoted, whereas anti-miR-218-5p suppressed, trophoblast invasion, EVT outgrowth, and enEVT differentiation. Furthermore, miR-218-5p accelerated spiral artery remodeling in a decidua-placenta co-culture. The effect of miR-218-5p was mediated by the suppression of transforming growth factor (TGF)-β2 signaling. Silencing of TGFB2 mimicked, whereas treatment with TGF-β2 partially reversed, the effects of miR-218-5p. Taken together, these findings demonstrate that miR-218-5p promotes trophoblast invasion and enEVT differentiation through a novel miR-218-5p-TGF-β2 pathway. This study elucidates the role of an miRNA in enEVT differentiation and spiral artery remodeling and suggests that downregulation of miR-218-5p contributes to PE development.

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Elucidating the Pathogenesis of Pre-eclampsia Using In Vitro Models of Spiral Uterine Artery Remodelling

Cited by 50 publications

References 101 publications

Overlapping Pathogenic Signalling Pathways and Biomarkers in Preeclampsia and Cardiovascular Disease

Overlapping Pathogenic Signalling Pathways and Biomarkers in Preeclampsia and Cardiovascular Disease

LRP6 is involved in the proliferation, migration and invasion of trophoblast cells via miR‑346

MicroRNA-218-5p Promotes Endovascular Trophoblast Differentiation and Spiral Artery Remodeling

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