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Hypertension Research : Official... Aug 2023Preeclampsia is a hypertensive disorder in pregnancy characterized by placental malperfusion and subsequent multi-organ injury. It accounts for approximately 14% of... (Review)
Review
Preeclampsia is a hypertensive disorder in pregnancy characterized by placental malperfusion and subsequent multi-organ injury. It accounts for approximately 14% of maternal deaths and 10-25% of perinatal deaths globally. In addition, preeclampsia has been attracting attentions for its association with risks for developing chronic diseases in later life for both mother and child. This mini-review discusses on latest knowledge on prediction, prevention, management, and long-term outcomes of preeclampsia and also touches on association between COVID-19 and preeclampsia. HTN hypertension, HDP hypertensive disorders of pregnancy, PE preeclampsia, BP blood pressure, cfDNA cell-free DNA, ST2 human suppression of tumorigenesis 2, sFlt-1 soluble fms-like tyrosine kinase-1, PIGF placental growth factor, VEGF vascular endothelial growth factor, VEGFR VEGF receptor, TGFβ transforming growth factor β, ENG endoglin, sENG soluble ENG, PRES posterior reversible encephalopathy syndrome, AKI acute kidney injury, CVD cardiovascular disease, ESKD end-stage kidney disease, ACE angiotensinogen converting enzyme, Ang angiotensin.
Topics: Female; Humans; Pregnancy; Biomarkers; COVID-19; Endoglin; Hypertension; Placenta; Placenta Growth Factor; Posterior Leukoencephalopathy Syndrome; Pre-Eclampsia; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1
PubMed: 37268721
DOI: 10.1038/s41440-023-01323-w -
International Journal of Molecular... Jul 2023Preeclampsia (PE) is a pregnancy-specific disorder affecting 4-10% of all expectant women. It greatly increases the risk of maternal and foetal death. Although the main... (Review)
Review
Preeclampsia (PE) is a pregnancy-specific disorder affecting 4-10% of all expectant women. It greatly increases the risk of maternal and foetal death. Although the main symptoms generally appear after week 20 of gestation, scientific studies indicate that the mechanism underpinning PE is initiated at the beginning of gestation. It is known that the pathomechanism of preeclampsia is strongly related to inflammation and oxidative stress, which influence placentation and provoke endothelial dysfunction in the mother. However, as of yet, no "key players" regulating all these processes have been discovered. This might be why current therapeutic strategies intended for prevention or treatment are not fully effective, and the only effective method to stop the disease is the premature induction of delivery, mostly by caesarean section. Therefore, there is a need for further research into new pharmacological strategies for the treatment and prevention of preeclampsia. This review presents new preventive methods and therapies for PE not yet recommended by obstetrical and gynaecological societies. As many of these therapies are in preclinical studies or under evaluation in clinical trials, this paper reports the molecular targets of the tested agents or methods.
Topics: Pregnancy; Female; Humans; Pre-Eclampsia; Cesarean Section; Placentation; Oxidative Stress; Vascular Endothelial Growth Factor Receptor-1
PubMed: 37569476
DOI: 10.3390/ijms241512100 -
Nature Communications Aug 2023The extravillous trophoblast cell lineage is a key feature of placentation and successful pregnancy. Knowledge of transcriptional regulation driving extravillous...
The extravillous trophoblast cell lineage is a key feature of placentation and successful pregnancy. Knowledge of transcriptional regulation driving extravillous trophoblast cell development is limited. Here, we map the transcriptome and epigenome landscape as well as chromatin interactions of human trophoblast stem cells and their transition into extravillous trophoblast cells. We show that integrating chromatin accessibility, long-range chromatin interactions, transcriptomic, and transcription factor binding motif enrichment enables identification of transcription factors and regulatory mechanisms critical for extravillous trophoblast cell development. We elucidate functional roles for TFAP2C, SNAI1, and EPAS1 in the regulation of extravillous trophoblast cell development. EPAS1 is identified as an upstream regulator of key extravillous trophoblast cell transcription factors, including ASCL2 and SNAI1 and together with its target genes, is linked to pregnancy loss and birth weight. Collectively, we reveal activation of a dynamic regulatory network and provide a framework for understanding extravillous trophoblast cell specification in trophoblast cell lineage development and human placentation.
Topics: Pregnancy; Female; Humans; Trophoblasts; Chromatin; Placentation; Cell Differentiation; Transcription Factors; Cell Lineage; Placenta; Basic Helix-Loop-Helix Transcription Factors
PubMed: 37563143
DOI: 10.1038/s41467-023-40424-5 -
Cell Reports Jun 2023Ruptured ectopic pregnancy (REP), a pregnancy complication caused by aberrant implantation, deep invasion, and overgrowth of embryos in fallopian tubes, could lead to...
Ruptured ectopic pregnancy (REP), a pregnancy complication caused by aberrant implantation, deep invasion, and overgrowth of embryos in fallopian tubes, could lead to rupture of fallopian tubes and accounts for 4%-10% of pregnancy-related deaths. The lack of ectopic pregnancy phenotypes in rodents hampers our understanding of its pathological mechanisms. Here, we employed cell culture and organoid models to investigate the crosstalk between human trophoblast development and intravillous vascularization in the REP condition. Compared with abortive ectopic pregnancy (AEP), the size of REP placental villi and the depth of trophoblast invasion are correlated with the extent of intravillous vascularization. We identified a key pro-angiogenic factor secreted by trophoblasts, WNT2B, that promotes villous vasculogenesis, angiogenesis, and vascular network expansion in the REP condition. Our results reveal the important role of WNT-mediated angiogenesis and an organoid co-culture model for investigating intricate communications between trophoblasts and endothelial/endothelial progenitor cells.
Topics: Pregnancy; Humans; Female; Trophoblasts; Placenta; Pregnancy, Ectopic; Embryo Implantation; Organoids
PubMed: 37224015
DOI: 10.1016/j.celrep.2023.112546 -
Science Advances Oct 2023The maternal microbiome is an important regulator of gestational health, but how it affects the placenta as the interface between mother and fetus remains unexplored....
The maternal microbiome is an important regulator of gestational health, but how it affects the placenta as the interface between mother and fetus remains unexplored. Here, we show that the maternal gut microbiota supports placental development in mice. Depletion of the maternal gut microbiota restricts placental growth and impairs feto-placental vascularization. The maternal gut microbiota modulates metabolites in the maternal and fetal circulation. Short-chain fatty acids (SCFAs) stimulate cultured endothelial cell tube formation and prevent abnormalities in placental vascularization in microbiota-deficient mice. Furthermore, in a model of maternal malnutrition, gestational supplementation with SCFAs prevents placental growth restriction and vascular insufficiency. These findings highlight the importance of host-microbial symbioses during pregnancy and reveal that the maternal gut microbiome promotes placental growth and vascularization in mice.
Topics: Pregnancy; Mice; Female; Animals; Placentation; Placenta; Microbiota; Fetus; Gastrointestinal Microbiome
PubMed: 37801498
DOI: 10.1126/sciadv.adk1887 -
Nature May 2024The gut microbiota operates at the interface of host-environment interactions to influence human homoeostasis and metabolic networks. Environmental factors that...
The gut microbiota operates at the interface of host-environment interactions to influence human homoeostasis and metabolic networks. Environmental factors that unbalance gut microbial ecosystems can therefore shape physiological and disease-associated responses across somatic tissues. However, the systemic impact of the gut microbiome on the germline-and consequently on the F offspring it gives rise to-is unexplored. Here we show that the gut microbiota act as a key interface between paternal preconception environment and intergenerational health in mice. Perturbations to the gut microbiota of prospective fathers increase the probability of their offspring presenting with low birth weight, severe growth restriction and premature mortality. Transmission of disease risk occurs via the germline and is provoked by pervasive gut microbiome perturbations, including non-absorbable antibiotics or osmotic laxatives, but is rescued by restoring the paternal microbiota before conception. This effect is linked with a dynamic response to induced dysbiosis in the male reproductive system, including impaired leptin signalling, altered testicular metabolite profiles and remapped small RNA payloads in sperm. As a result, dysbiotic fathers trigger an elevated risk of in utero placental insufficiency, revealing a placental origin of mammalian intergenerational effects. Our study defines a regulatory 'gut-germline axis' in males, which is sensitive to environmental exposures and programmes offspring fitness through impacting placenta function.
Topics: Animals; Female; Male; Mice; Pregnancy; Dysbiosis; Fathers; Gastrointestinal Microbiome; Leptin; Mice, Inbred C57BL; Placenta; Placental Insufficiency; Pregnancy Outcome; Prenatal Injuries; Signal Transduction; Spermatozoa; Testis; Disease Susceptibility
PubMed: 38693261
DOI: 10.1038/s41586-024-07336-w -
Science Advances Nov 2023Inflammation-associated insulin resistance is a key trigger of gestational diabetes mellitus (GDM), but the underlying mechanisms and effective interventions remain...
Inflammation-associated insulin resistance is a key trigger of gestational diabetes mellitus (GDM), but the underlying mechanisms and effective interventions remain unclear. Here, we report the association of placental inflammation (tumor necrosis factor-α) and abnormal maternal glucose metabolism in patients with GDM, and a high fermentable dietary fiber (HFDF; ) could reduce GDM development through gut flora-short-chain fatty acid-placental inflammation axis in GDM mouse model. Mechanistically, HFDF increases abundances of and butyrate, reduces placental-derived inflammation by enhancing gut barrier and inhibiting the transfer of bacterial-derived lipopolysaccharide, and ultimately resists high-fat diet-induced insulin resistance. and butyrate have similar anti-GDM and anti-placental inflammation effects, and they can ameliorate placental function and pregnancy outcome effects probably by dampening placental immune dysfunction. These findings demonstrate the involvement of important placental inflammation-related mechanisms in the progression of GDM and the great potential of HFDFs to reduce susceptibility to GDM through gut-flora-placenta axis.
Topics: Animals; Mice; Pregnancy; Humans; Female; Diabetes, Gestational; Placenta; Insulin Resistance; Butyrates; Inflammation
PubMed: 37922350
DOI: 10.1126/sciadv.adi7337 -
Advanced Science (Weinheim,... Sep 2023The interaction between trophoblasts, stroma cells, and immune cells at the maternal-fetal interface constitutes the functional units of the placenta, which is crucial...
The interaction between trophoblasts, stroma cells, and immune cells at the maternal-fetal interface constitutes the functional units of the placenta, which is crucial for successful pregnancy outcomes. However, the investigation of this intricate interplay is restricted due to the absence of efficient experimental models. To address this challenge, a robust, reliable methodology for generating placenta villi organoids (PVOs) from early, late, or diseased pregnancies using air-liquid surface culture is developed. PVOs contain cytotrophoblasts that can self-renew and differentiate directly, along with stromal elements that retain native immune cells. Analysis of scRNA sequencing and WES data reveals that PVOs faithfully recapitulate the cellular components and genetic alterations of the corresponding source tissue. Additionally, PVOs derived from patients with preeclampsia exhibit specific pathological features such as inflammation, antiangiogenic imbalance, and decreased syncytin expression. The PVO-based propagation of primary placenta villi should enable a deeper investigation of placenta development and exploration of the underlying pathogenesis and therapeutics of placenta-originated diseases.
Topics: Pregnancy; Female; Humans; Placenta; Chorionic Villi; Placentation; Trophoblasts; Organoids
PubMed: 37438660
DOI: 10.1002/advs.202301565 -
Human Reproduction Update Nov 2023Estrogens regulate disparate female physiological processes, thus ensuring reproduction. Altered estrogen levels and signaling have been associated with increased risks... (Review)
Review
The pathophysiological role of estrogens in the initial stages of pregnancy: molecular mechanisms and clinical implications for pregnancy outcome from the periconceptional period to end of the first trimester.
BACKGROUND
Estrogens regulate disparate female physiological processes, thus ensuring reproduction. Altered estrogen levels and signaling have been associated with increased risks of pregnancy failure and complications, including hypertensive disorders and low birthweight babies. However, the role of estrogens in the periconceptional period and early pregnancy is still understudied.
OBJECTIVE AND RATIONALE
This review aims to summarize the current evidence on the role of maternal estrogens during the periconceptional period and the first trimester of pregnancies conceived naturally and following ART. Detailed molecular mechanisms and related clinical impacts are extensively described.
SEARCH METHODS
Data for this narrative review were independently identified by seven researchers on Pubmed and Embase databases. The following keywords were selected: 'estrogens' OR 'estrogen level(s)' OR 'serum estradiol' OR 'estradiol/estrogen concentration', AND 'early pregnancy' OR 'first trimester of pregnancy' OR 'preconceptional period' OR 'ART' OR 'In Vitro Fertilization (IVF)' OR 'Embryo Transfer' OR 'Frozen Embryo Transfer' OR 'oocyte donation' OR 'egg donation' OR 'miscarriage' OR 'pregnancy outcome' OR 'endometrium'.
OUTCOMES
During the periconceptional period (defined here as the critical time window starting 1 month before conception), estrogens play a crucial role in endometrial receptivity, through the activation of paracrine/autocrine signaling. A derailed estrogenic milieu within this period seems to be detrimental both in natural and ART-conceived pregnancies. Low estrogen levels are associated with non-conception cycles in natural pregnancies. On the other hand, excessive supraphysiologic estrogen concentrations at time of the LH peak correlate with lower live birth rates and higher risks of pregnancy complications. In early pregnancy, estrogen plays a massive role in placentation mainly by modulating angiogenic factor expression-and in the development of an immune-tolerant uterine micro-environment by remodeling the function of uterine natural killer and T-helper cells. Lower estrogen levels are thought to trigger abnormal placentation in naturally conceived pregnancies, whereas an estrogen excess seems to worsen pregnancy development and outcomes.
WIDER IMPLICATIONS
Most current evidence available endorses a relation between periconceptional and first trimester estrogen levels and pregnancy outcomes, further depicting an optimal concentration range to optimize pregnancy success. However, how estrogens co-operate with other factors in order to maintain a fine balance between local tolerance towards the developing fetus and immune responses to pathogens remains elusive. Further studies are highly warranted, also aiming to identify the determinants of estrogen response and biomarkers for personalized estrogen administration regimens in ART.
Topics: Pregnancy; Female; Humans; Pregnancy Outcome; Estrogens; Pregnancy Trimester, First; Placentation; Fertilization in Vitro; Estradiol
PubMed: 37353909
DOI: 10.1093/humupd/dmad016 -
Annual Review of Nutrition Aug 2023The placenta is the gatekeeper between the mother and the fetus. Over the first trimester of pregnancy, the fetus is nourished by uterine gland secretions in a process... (Review)
Review
The placenta is the gatekeeper between the mother and the fetus. Over the first trimester of pregnancy, the fetus is nourished by uterine gland secretions in a process known as histiotrophic nutrition. During the second trimester of pregnancy, placentation has evolved to the point at which nutrients are delivered to the placenta via maternal blood (hemotrophic nutrition). Over gestation, the placenta must adapt to these variable nutrient supplies, to alterations in maternal physiology and blood flow, and to dynamic changes in fetal growth rates. Numerous questions remain about the mechanisms used to transport nutrients to the fetus and the maternal and fetal determinants of this process. Growing data highlight the ability of the placenta to regulate this process. As new technologies and omics approaches are utilized to study this maternofetal interface, greater insight into this unique organ and its impact on fetal development and long-term health has been obtained.
Topics: Female; Pregnancy; Humans; Placenta; Placentation; Pelvis; Uterus; Mothers
PubMed: 37603428
DOI: 10.1146/annurev-nutr-061121-085246