Placenta–heart axis: abnormal cardiovascular development and VEGF expression after perigestational alcohol intake at mid-gestation in mouse

Abstract

The normal development of cardiovascular-placenta axis depends on VEGF and KDR expressions. Previously, perigestational alcohol consumption at mouse organogenesis produces altered VEGF expression in the embryo and labyrinth associated with vascular anomalies.Objectives: The aims were to assess the histopathology, ultrastructure and proliferation of the ventricular and atrial myocardium and endocardium of fetal heart, and morphogenesis of labyrinth (L) and junctional zone (JZ), and to evaluate the VEGF/KDR expression in the heart-placental axis at day 13 of gestation after cessation of perigestational alcohol intake at day 10 of gestation.Methods: Ethanol 10% in drinking water was administered to murine CF-1 females for 15 days before and up to day 10 of gestation (D10), and pregnancy continued with water until day 13 (treated females (TF). Control females (CF) consumed water. Morphological studies and VEGF/KDR expressions were performed in fetal hearts and placentas by histology (H-E and PAS), TEM, immunohistochemistry and western blot.Results: The cardiac wall thickness was reduced (p<0.001) in 79% TF-fetuses compared to 13% of CF-fetuses. Hearts of TF-fetuses had reduced proliferation (Ki67) (p<0.05 vs controls), disrupted cardiomyocytic myofilaments and mitochondrial reduced size (p<0.01), vs CF-fetuses). TF-labyrinthine thickness was reduced while junctional zone (JZ) increased respect to controls. TF-labyrinth was disorganized, had wide maternal blood spaces and reduced fetal capilarization. Myocardial VEGF expression was reduced in TF-fetuses (p<0.001 vs controls). Placental VEGF expression increased (p<0.05) in labyrinth and JZ. KDR was expressed in endocardium, pericardium and cardiac cushions, labyrinth and JZ, without differences between groups.Conclusions: Perigestational alcohol consumption up to organogenesis induced hypotrophic fetal hearts and diminished VEGF expression, while labyrinthine and JZ abnormalities were found with high VEGF expression. Despite of alcohol intake cessation at D10, defects of fetal cardiac-placental axis appeared to be associated to VEGF expression in an opposite and tissue-dependent manner.