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.
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.
El consumo crónico, moderado-severo, de alcohol durante la gestación, de alta prevalencia en Argentina y en el mundo, produce retraso del crecimiento intrauterino (RCIU), elevado riesgo de desarrollo del Trastorno del Espectro Alcohólico Fetal (FASD) y diversas enfermedades en la descendencia. En los últimos años, se ha propuesto que tanto el RCIU como las cardiopatías congénitas y enfermedades crónicas del adulto típicas del FASD, están asociadas o causadas por alteración placentaria. La exposición a alcohol puede afectar, junto con el epigenoma de la placenta, diversos mecanismos moleculares de la angiogénesis placentaria en estadios tempranos y/o a término. Sin embargo, aún son poco conocidos los efectos del consumo perigestacional moderado de alcohol sobre el desarrollo fetal. Este tipo de ingesta, desde antes de la preñez y hasta la organogénesis temprana, representa a una mujer consumidora de tipo social que continúa con la ingesta durante el primer mes de embarazo, cuando aún no toma conocimiento sobre su estado de gravidez. En este contexto, nuestro laboratorio ha establecido un modelo murino experimental de consumo materno perigestacional de alcohol para estudiar los efectos en el desarrollo embrio-feto-placentario, y los mecanismos moleculares involucrados. En relación a ello, nuestra reciente evidencia muestra que el consumo perigestacional de alcohol hasta etapas tempranas de la gestación induce anormalidades morfológicas y esqueléticas y cardiopatía fetal junto con defectos del crecimiento, vascularización deficiente y alteraciones en la expresión y actividad de factores angiogénicos de la placenta. En este marco de estudios, sugerimos que las manifestaciones del FASD se originan tempranamente y están vinculadas con placentación temprana anómala, jugando en ello un papel preponderante los defectos de la vascularización de la cara materna (decidua) y del desarrollo y crecimiento de la cara fetal (laberinto) durante la gestación temprana a tardía en el modelo murino de exposición materna a alcohol.
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