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Review
. 2022 Feb 2:12:815760.
doi: 10.3389/fphys.2021.815760. eCollection 2021.

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

Gisela Soledad Gualdoni  1 , Patricia Verónica Jacobo  1 , Camila Barril  1 , Martín Ricardo Ventureira  1 , Elisa Cebral  1
Affiliations
Review

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

Gisela Soledad Gualdoni et al. Front Physiol. .

Abstract

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.

Keywords: VEGF system; mouse; perigestational alcohol; placenta; vascular abnormality.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Schematic diagram of the role of VEGF system in the placentation. The vascular endothelial growth factor (VEGF) activates the membrane kinase insert domain receptor (KDR) by phosphorylation, triggering specific signaling cascades. By increasing intracellular calcium (Ca++) and calmodulin (CaM) VEGF-KDR binding induces the expression and activity of nitric oxide synthase (NOS) to produce increase of nitric oxide (NO), a strong inducer of increased vascular permeability, vasodilation, cell migration and differentiation. The other via of VEGF-KDR activation, related to fosfatidil inositol 4,5-bisfosfato (PIP-2) and diacylglycerol (DAG), leads to the transcription of metalloproteinases (MMPs). MMPs are secreted to the extracellular matrix (ECM) where, among other functions, degrade and remodel the ECM and release the ECM-sequestered VEGF by cleaving proteins that retain it in the matrix. The soluble receptor tyrosine kinase similar to fms-1 (sFLT-1) can prevent the binding of VEGF to KDR, thus decreasing it pro-angiogenic and survival activity. VEGF expression can be modified by NO, prostaglandins (PGs), hypoxia inducible factor (HIF-1α), reactive oxygen species (ROS), reduced glutathione (GSH), among other factors. In overall, placental activated VEGF system mediates the angiogenesis-vascularization during placentation.
FIGURE 2
FIGURE 2
Proposed mechanisms of abnormal early placentation and vascularization and long-term impact to placenta produced by perigestational alcohol consumption, in the mouse model. Perigestational alcohol (OH) intake up to gastrulation-organogenesis [day 8 (D8) (A) and 10 (D10) (B), disrupts the maternal spiral artery (ma) remodeling of mesometrial decidua (MD), and alters the ectoplacental cone (EPC) (A) and subsequent development of trophoblastic zone (Tz) of the early placenta (B). Consequently, after cessation of alcohol ingestion (day 11, D11), abnormal trophoblast invasion and endothelial replacement may occur (C), leading to abnormal structure and function of the placenta at term (D). The placental abnormalities can be originated in altered angiogenesis-vascularization of decidual-trophoblastic tissues (E,G) during perigestational alcohol exposure (B). Alcohol and/or its metabolites [acetaldehyde, AcT, reactive oxygen species (ROS)] impact on the early placentation processes, including changes in uNK cells. Consequently, diminished junctional trophoblast differentiation and low labyrinthine growth and vascularization can occur (G). The decidual-trophoblastic abnormalities can be associated with altered endothelial nitric oxide synthase (eNOS) and metalloproteinases (MMP)-2 and/or MMP-9 expression/activity due to abnormal vascular endothelial growth factor (VEGF) expression and KDR activation (pKDR) or increased FLT-1 (F,H). The disrupted VEGF-receptor-NOS-MMPs mechanisms are linked to hypoxia and increased HIF-1α, and reactive oxygen species and/or reactive nitrogen species (ROS/RNS) production. Sm, smooth muscle cells of spiral arteries; ec, endothelial cells; cTB: chorionic trophoblastic cells; SpT, spongiotrophoblastic cells; GC, glycogen cells; TGC, trophoblast giant cells; fv, fetal vessels; Lab, labyrinth; JZ, junctional zone; TB, trophoblast; ECM, extracellular matrix; AMD, antimesometrial decidua.
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References

    1. Acevedo C. G., Carrasco G., Burotto M., Rojas S., Bravo I. (2001). Ethanol inhibits L-arginine uptake and enhances NO formation in human placenta. Life Sci. 68 2893–2903. 10.1016/s0024-3205(01)01070-0 - DOI - PubMed
    1. Adamson S. L., Lu Y., Whiteley K. J., Holmyard D., Hemberger M., Pfarrer C., et al. (2002). Interactions between trophoblast cells and the maternal and fetal circulation in the mouse placenta. Dev. Biol. 250 358–373. 10.1006/dbio.2002.0773 - DOI - PubMed
    1. Agaoglu O. K., Agaoglu A. R., Guzeloglu A., Aslan S., Kurar E., Kayis S. A., et al. (2016). Gene expression profiles of some cytokines, growth factors, receptors, and enzymes (GM-CSF, IFNγ, MMP-2, IGF-II, EGF, TGF-β, IGF-IIR) during pregnancy in the cat uterus. Theriogenology 85 638–644. 10.1016/j.theriogenology.2015.10.001 - DOI - PubMed
    1. Alexander C. M., Hansell E. J., Behrendtsen O., Flannery M. L., Kishnani N. S., Hawkes S. P., et al. (1996). Expression and function of matrix metalloproteinases and their inhibitors at the maternal-embryonic boundary during mouse embryo implantation. Development 122 1723–1736. 10.1242/dev.122.6.1723 - DOI - PubMed
    1. Aliyu M. H., Lynch O., Nana P. N., Alio A. P., Wilson R. E., Marty P. J., et al. (2011). Alcohol consumption during pregnancy and risk of placental abruption and placenta previa. Matern. Child. Health. J 15 670–676. 10.1007/s10995-010-0615-6 - DOI - PubMed

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