Perigestational alcohol consumption induces altered early placentation and organogenic embryo growth restriction by disruption of trophoblast angiogenic factors

Gualdoni, Gisela Soledad; Ventureira, Martín Ricardo; Coll, Tamara Anahí; Palomino, Wilder A.; Barbeito, Claudio Gustavo; Cebral, Elisa

doi:10.1016/j.rbmo.2020.10.015

Cited by 14 publications

(34 citation statements)

References 82 publications

(93 reference statements)

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“…Evidence is currently lacking, in animal models, to explain the effects and cellular-molecular pathways responsible for late placental abnormalities induced by perigestational alcohol consumption (PAC) until early gestation (Gårdebjer et al, 2014;Kalisch-Smith and Moritz, 2017;Kalisch-Smith et al, 2019). Here, in a mouse model, we propose that PAC up to organogenesis disrupts the early decidual-trophoblastic development and vascularization (Figures 2A,B; Perez-Tito et al, 2014;Coll et al, 2018;Ventureira et al, 2019;Gualdoni G. S. et al, 2021), leading to incomplete maternal vascular remodeling due to trophoblast invasion defects (Figure 2C), and later, to abnormal placenta (Figure 2D). The placental abnormalities can be originated in altered angiogenesis-vascularization of decidual-trophoblastic tissues (E,G) during perigestational alcohol exposure (B).…”

Section: Perigestational Alcohol Consumption Up To Early Gestation: E...mentioning

confidence: 93%

“…Expansion of the uterus to accommodate the growing embryo and the maternal vascular establishment depend on MMP-2 and -9 (Sternlicht and Werb, 2001). At early mouse gestation, TGCs are positive for MMP-2 and MMP-9 expression (Alexander et al, 1996;Bany et al, 2000;Bai et al, 2005), while during organogenesis mainly MMP-9 participates in TGC-invasion and labyrinthine vascularization (Fontana et al, 2012;Gualdoni G. S. et al, 2021). VEGF up-regulates the MMP-2 and MMP-9 expression in human umbilical vein endothelial cells (Heo et al, 2010).…”

Section: Vascular Endothelial Growth Factor System During Placentationmentioning

confidence: 99%

“…VEGF up-regulates the MMP-2 and MMP-9 expression in human umbilical vein endothelial cells (Heo et al, 2010). Imbalances of VEGF system and subsequent alterations in MMP-2 and MMP-9 expression-activity take relevance in abnormal placentation (Gualdoni G. S. et al, 2021) and in various placentopathies (Amȃlinei et al, 2007;Cui et al, 2017).…”

Section: Vascular Endothelial Growth Factor System During Placentationmentioning

confidence: 99%

“…Perigestational moderate alcohol ingestion up to organogenesis in mouse produces protein nitration, lipid peroxidation and DNA damage in trophoblast-decidual tissue (Coll et al, 2018). As a result of alcohol-induced OS and decreased bioavailability of NO, insufficient early placental vascularization and arteriolar vasoconstriction can cause placental hypoxia (Acevedo et al, 2001;Wareing et al, 2006;Gualdoni G. S. et al, 2021).…”

Section: Pathophysiologic Mechanisms Involved In Alcohol-associated P...mentioning

confidence: 99%

“…Particularly, perigestational moderate alcohol consumption up to peri-implantation prevents blastocyst implantation and results in early pregnancy loss (Perez-Tito et al, 2014). Since maternal alcohol exposure can decrease the trophoblast migration/invasion leading to abnormal placental vascularization (Han et al, 2012), the link between placental vasculopathy and failure in the early decidualtrophoblast development and dysregulation of angiogenesisvascularization after perigestational alcohol ingestion up to organogenesis recently began to be studied in mouse models (Coll et al, 2018;Ventureira et al, 2019;Gualdoni G. S. et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

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Early Abnormal Placentation and Evidence of Vascular Endothelial Growth Factor System Dysregulation at the Feto-Maternal Interface After Periconceptional Alcohol Consumption

et al. 2022

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Adequate placentation, placental tissue remodeling and vascularization is essential for the success of gestation and optimal fetal growth. Recently, it was suggested that abnormal placenta induced by maternal alcohol consumption may participate in fetal growth restriction and relevant clinical manifestations of the Fetal Alcohol Spectrum Disorders (FASD). Particularly, periconceptional alcohol consumption up to early gestation can alter placentation and angiogenesis that persists in pregnancy beyond the exposure period. Experimental evidence suggests that abnormal placenta following maternal alcohol intake is associated with insufficient vascularization and defective trophoblast development, growth and function in early gestation. Accumulated data indicate that impaired vascular endothelial growth factor (VEGF) system, including their downstream effectors, the nitric oxide (NO) and metalloproteinases (MMPs), is a pivotal spatio-temporal altered mechanism underlying the early placental vascular alterations induced by maternal alcohol consumption. In this review we propose that the periconceptional alcohol intake up to early organogenesis (first trimester) alters the VEGF-NO-MMPs system in trophoblastic-decidual tissues, generating imbalances in the trophoblastic proliferation/apoptosis, insufficient trophoblastic development, differentiation and migration, deficient labyrinthine vascularization, and uncompleted remodelation and transformation of decidual spiral arterioles. Consequently, abnormal placenta with insufficiency blood perfusion, vasoconstriction and reduced labyrinthine blood exchange can be generated. Herein, we review emerging knowledge of abnormal placenta linked to pregnancy complications and FASD produced by gestational alcohol ingestion and provide evidence of the early abnormal placental angiogenesis-vascularization and growth associated to decidual-trophoblastic dysregulation of VEGF system after periconceptional alcohol consumption up to mid-gestation, in a mouse model.

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Section: Perigestational Alcohol Consumption Up To Early Gestation: E...mentioning

confidence: 93%

Section: Vascular Endothelial Growth Factor System During Placentationmentioning

confidence: 99%

Section: Vascular Endothelial Growth Factor System During Placentationmentioning

confidence: 99%

Section: Pathophysiologic Mechanisms Involved In Alcohol-associated P...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Early Abnormal Placentation and Evidence of Vascular Endothelial Growth Factor System Dysregulation at the Feto-Maternal Interface After Periconceptional Alcohol Consumption

et al. 2022

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Abnormal growth and morphogenesis of placenta at term is linked to adverse fetal development after perigestational alcohol consumption up to early gestation in mouse

Gualdoni

Pérez-Tito

Barril

et al. 2022

Birth Defects Research

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Background: Gestation alcohol consumption produces fetal growth restriction and malformations by affecting the embryo-fetal development. Recently a relationship between abnormal placentation and fetal malformation and intrauterine growth retardation has been suggested. However, the effects of perigestational alcohol ingestion up to early pregnancy on the placenta at term and its association with fetal abnormalities are little known. Methods: In female mice, ethanol 10% in water was administered for 15 days previous and up to days 4 (D4), 8 (D8), or 10 (D10) of gestation (TF), and gestation continues without ethanol exposure. Control females (CF) received ethanol-free water. At day 18, feto-placental units and implantation sites were studied.Results: TF had increased resorptions and only fetuses from D8-TF and D10-TF had significantly increased weights versus CF. D4 and D10-TFplacentas had significantly reduced weights. All TF had increased junctional zone (JZ) and reduced labyrinth (Lab) areas (PAS-histology and morphometry) compared with CF. Fetuses with mainly with craniofacial abnormalities and skeletal defects (Alizarin red staining), significantly increase; while the fetal bone density (alizarin color intensity, ImageJ) was reduced in D4, D8 and D10-TF versus CF. Although all TF-placentas were histo-structural affected, TF-abnormal fetuses had the most severe placental anomalies, with junctional abundant glycogenic cells into the labyrinth, disorganized labyrinthine vascularization with signs of leukocyte infiltrates and feto-maternal blood mix. Conclusions: Perigestational alcohol consumption up to early gestation induces at term fetal growth alterations, dysmorphology and defective skeleton, linked to deficient growth and abnormal morphogenesis of placenta, highlighting insight into the prenatal etiology of FASD.

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Fetal growth restriction exhibits various mTOR signaling in different regions of mouse placentas with altered lipid metabolism

Dong,

Xu,

Qian

et al. 2024

Cell Biol Toxicol

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Fetal growth restriction (FGR) is a common complication of pregnancy and can have significant impact on obstetric and neonatal outcomes. Increasing evidence has shown that the inhibited mechanistic target of rapamycin (mTOR) signaling in placenta is associated with FGR. However, interpretation of existing research is limited due to inconsistent methodologies and varying understanding of the mechanism by which mTOR activity contributes to FGR. Hereby, we have demonstrated that different anatomic regions of human and mouse placentas exhibited different levels of mTOR activity in normal compared to FGR pregnancies. When using the rapamycin-induced FGR mouse model, we found that placentas of FGR pregnancies exhibited abnormal morphological changes and reduced mTOR activity in the decidual-junctional layer. Using transcriptomics and lipidomics, we revealed that lipid and energy metabolism was significantly disrupted in the placentas of FGR mice. Finally, we demonstrated that maternal physical exercise during gestation in our FGR mouse model was associated with increased fetal and placental weight as well as increased placental mTOR activity and lipid metabolism. Collectively, our data indicate that the inhibited placental mTOR signaling contributes to FGR with altered lipid metabolism in mouse placentas, and maternal exercise could be an effective method to reduce the occurrence of FGR or alleviate the adverse outcomes associated with FGR. Graphical Abstract Human and mouse placentas have different mTOR signaling activities in different anatomic regions in normal and FGR pregnancies. Pregnant mice with FGR induced by rapamycin show smaller placentas, decreased mTOR activity in DJ layer of placenta and altered lipid metabolism. Maternal exercise partially alleviates the abnormal outcomes of FGR model.

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Perigestational alcohol consumption induces altered early placentation and organogenic embryo growth restriction by disruption of trophoblast angiogenic factors

Cited by 14 publications

References 82 publications

Early Abnormal Placentation and Evidence of Vascular Endothelial Growth Factor System Dysregulation at the Feto-Maternal Interface After Periconceptional Alcohol Consumption

Early Abnormal Placentation and Evidence of Vascular Endothelial Growth Factor System Dysregulation at the Feto-Maternal Interface After Periconceptional Alcohol Consumption

Abnormal growth and morphogenesis of placenta at term is linked to adverse fetal development after perigestational alcohol consumption up to early gestation in mouse

Fetal growth restriction exhibits various mTOR signaling in different regions of mouse placentas with altered lipid metabolism

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