Effect of glucocorticoids on mechanisms of placental angiogenesis

Ozmen, Asli; Unek, Gozde; Korgun, Emin Türkay

doi:10.1016/j.placenta.2017.02.015

Cited by 26 publications

(12 citation statements)

References 90 publications

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“…There is strong evidence from animal studies that prolonged or excessive exposure to natural or synthetic glucocorticoids causes fetal growth impairment and programming of cardiovascular, metabolic and neuroendocrine disorders (Seckl andMeaney, 2004, Kemp, et al, 2016). Previous studies show that glucocorticoids administered in mid-or late gestation affect placental development and gene expression in the placenta in a sex-dependent manner (Vaughan, et al, 2015, Lee, et al, 2017, Ozmen, et al, 2017. The current study is the first to demonstrate an effect of pre-implantation glucocorticoids on later fetal developmental outcomes.…”

Section: Discussionsupporting

confidence: 56%

Prednisolone in early pregnancy inhibits regulatory T cell generation and alters fetal and placental development in mice

Kieffer

Chin

Green

et al. 2020

Molecular Human Reproduction

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Corticosteroids have been utilised in the assisted reproduction setting with the expectation of suppressing aberrant immune activation and improving fertility in women. However, the effects of corticosteroids on fertility, and on pregnancy and offspring outcomes, are unclear. In this study, mice were administered prednisolone (1 mg/kg) or PBS daily in the pre-implantation phase, and effects on the adaptive immune response, the implantation rate, fetal development and postnatal outcomes were investigated. Prednisolone disrupted the expected expansion of CD4+ T cells in early pregnancy, inhibiting generation of both regulatory T cells (Treg cells) and effector T cells and suppressing IFNG required for T cell functional competence. Prednisolone caused an 8–20% increase in the embryo implantation rate and increased the number of viable pups per litter. In late gestation, fetal and placental weights were reduced in a litter size-dependent manner, and the canonical inverse relationship between litter size and fetal weight was lost. The duration of pregnancy was extended by ~ 0.5 day and birth weight was reduced by ~ 5% after prednisolone treatment. Viability of prednisolone-exposed offspring was comparable to controls, but body weight was altered in adulthood, particularly in male offspring. Thus, while prednisolone given in the pre-implantation phase in mice increases maternal receptivity to implantation and resource investment in fetal growth, there is a trade-off in long-term consequences for fetal development, birth weight and offspring health. These effects are associated with, and likely caused by, prednisolone suppression of the adaptive immune response at the outset of pregnancy.

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Section: Discussionsupporting

confidence: 56%

Prednisolone in early pregnancy inhibits regulatory T cell generation and alters fetal and placental development in mice

Kieffer

Chin

Green

et al. 2020

Molecular Human Reproduction

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“…Dexamethasone promotes the expression of type I collagen, alkaline phosphatase, osteocalcin, and bone sialoprotein [ 11 ]. However, dexamethasone has been found to inhibit the formation of blood vessels in the tumor microenvironment [ 12 ] and in embryological development [ 13 ]. Dexamethasone inhibits the protein expression and activity of eNOS, which is not conducive to angiogenesis and fetal development [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Hypoxia alleviates dexamethasone-induced inhibition of angiogenesis in cocultures of HUVECs and rBMSCs via HIF-1α

Chai

Shen

et al. 2020

Stem Cell Res Ther

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Background and aim: Inadequate vascularization is a challenge in bone tissue engineering because internal cells are prone to necrosis due to a lack of nutrient supply. Rat bone marrow-derived mesenchymal stem cells (rBMSCs) and human umbilical vein endothelial cells (HUVECs) were cocultured to construct prevascularized bone tissue in osteogenic induction medium (OIM) in vitro. The angiogenic capacity of HUVECs was limited in the coculture system. In this study, the effects of the components in the medium on HUVEC angiogenesis were analyzed. Methods: The coculture system was established in OIM. Alizarin red staining and alkaline phosphatase staining were used to assess the osteogenic ability of MSCs. A Matrigel tube assay was used to assess the angiogenic ability of HUVECs in vitro. The proliferation of HUVECs was evaluated by cell counting and CCK-8 assays, and migration was evaluated by the streaked plate assay. The expression levels of angiogenesis-associated genes and proteins in HUVECs were measured by qRT-PCR and Western blotting, respectively. Results: Dexamethasone in the OIM suppressed the proliferation and migration of HUVECs, inhibiting the formation of capillary-like structures. Our research showed that dexamethasone stimulated HUVECs to secrete tissue inhibitor of metalloproteinase (TIMP-3), which competed with vascular endothelial growth factor (VEGF-A) to bind to vascular endothelial growth factor receptor 2 (VEGFR2, KDR). This effect was related to inhibiting the phosphorylation of ERK and AKT, which are two downstream targets of KDR. However, under hypoxia, the enhanced expression of hypoxiainducible factor-1α (HIF-1α) decreased the expression of TIMP-3 and promoted the phosphorylation of KDR, improving HUVEC angiogenesis in the coculture system. Conclusion: Coculture of hypoxia-preconditioned HUVECs and MSCs showed robust angiogenesis and osteogenesis in OIM, which has important implications for prevascularization in bone tissue engineering in the future.

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“…Women suffering with chronic stressors during pregnancy have increased risk for adverse pregnancy outcomes such as spontaneous abortion (SA), 1–3 intrauterine growth restriction (IUGR), 4,5 and preeclampsia (PE). 4,6 Glucocorticoids regulate gene expression by binding the glucocorticoid receptor (GR) and affecting gene transcription.…”

Section: | Introductionmentioning

confidence: 99%

“…4,6 Glucocorticoids regulate gene expression by binding the glucocorticoid receptor (GR) and affecting gene transcription. 7 Placental trophoblast cells express high levels of the GR 8,9 and are responsive to the stress hormone, cortisol.…”

Section: | Introductionmentioning

confidence: 99%

Cortisol inhibits CSF2 and CSF3 via DNA methylation and inhibits invasion in first‐trimester trophoblast cells

Smith

Witte

McGee

et al. 2017

American J Rep Immunol

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Problem Heightened maternal stress affects trophoblast function and increases risk for adverse pregnancy outcomes. Methods of Study Studies were performed using the first-trimester trophoblast cell line, Sw.71. Cytokines were quantified using qPCR and ELISA. Epigenetic regulation of cytokines was characterized by inhibiting histone deacetylation (1 μmol/L suberoylanilide hydroxamic acid [SAHA]) or methylation (5 μmol/L 5-azacytidine), or with chromatin immunoprecipitation (ChIP) with a pan-acetyl histone-3 antibody. Invasion assays used Matrigel chambers. Results Cortisol inhibited expression of CSF2 (GM-CSF) and CSF3 (G-CSF) in trophoblast cells. Cortisol-associated inhibition was dependent on DNA methylation and was not affected by acetylation. There was also a modest decrease in trophoblast invasion, not dependent on loss of CSFs. Conclusion In first-trimester trophoblast cells, the physiological glucocorticoid, cortisol, inhibited two cytokines with roles in placental development and decreased trophoblast invasion. Cortisol-associated changes in trophoblast function could increase the risk for immune-mediated abortion or other adverse pregnancy outcomes.

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Effect of glucocorticoids on mechanisms of placental angiogenesis

Cited by 26 publications

References 90 publications

Prednisolone in early pregnancy inhibits regulatory T cell generation and alters fetal and placental development in mice

Prednisolone in early pregnancy inhibits regulatory T cell generation and alters fetal and placental development in mice

Hypoxia alleviates dexamethasone-induced inhibition of angiogenesis in cocultures of HUVECs and rBMSCs via HIF-1α

Cortisol inhibits CSF2 and CSF3 via DNA methylation and inhibits invasion in first‐trimester trophoblast cells

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