Acute alcohol exposure during mouse gastrulation alters lipid metabolism in placental and heart development: Folate prevention.

Background: Embryonic acute exposure to ethanol (EtOH), lithium, and homocysteine (HCy) induces cardiac defects at the time of exposure; folic acid (FA) supplementation protects normal cardiogenesis (Han et al., , ; Serrano et al., ).

Embryonic exposures of lithium and homocysteine and folate protection affect lipid metabolism during mouse cardiogenesis and placentation.

Embryonic exposures can increase the risk of congenital cardiac birth defects and adult disease. The present study identifies the predominant pathways modulated by an acute embryonic mouse exposure during gastrulation to lithium or homocysteine that induces cardiac defects. High dose periconceptional folate supplementation normalized development.

Changes in vitelline and utero-placental hemodynamics: implications for cardiovascular development.

Analyses of cardiovascular development have shown an important interplay between heart function, blood flow, and morphogenesis of heart structure during the formation of a four-chambered heart. It is known that changes in vitelline and placental blood flow seemingly contribute substantially to early cardiac hemodynamics. This suggests that in order to understand mammalian cardiac structure-hemodynamic functional relationships, blood flow from the extra-embryonic circulation needs to be taken into account and its possible impact on cardiogenesis defined.

Evaluation of prenatal risk factors for prediction of outcome in right heart lesions: CVP score in fetal right heart defects.

Objective: To determine the prenatal variables predicting the risk of perinatal death in congenital right heart defects.

Methods: Retrospective analysis of 28 fetuses with right heart defects was performed. Logistic regression analyses were performed to obtain odds ratios (OR) for the relationship between the risk of death and echocardiographic parameters.

Ethanol exposure alters early cardiac function in the looping heart: a mechanism for congenital heart defects?

Alcohol-induced congenital heart defects are frequently among the most life threatening and require surgical correction in newborns. The etiology of these defects, collectively known as fetal alcohol syndrome, has been the focus of much study, particularly involving cellular and molecular mechanisms. Few studies have addressed the influential role of altered cardiac function in early embryogenesis because of a lack of tools with the capability to assay tiny beating hearts.

Environmental origins of congenital heart disease: the heart-placenta connection.

Although the mammalian embryo is well protected in the uterus, environmental chemicals, drugs, and maternal nutritional imbalances can interfere with regulatory pathways directing placental and embryonic development early in gestation. Embryonic cells are most susceptible to environmental influences during cellular specification and differentiation stages. Because biochemical differentiation precedes morphological outcome often by days, the period of susceptibility to environmental chemicals expectedly precedes visible morphogenic effects.

The heart-placenta axis in the first month of pregnancy: induction and prevention of cardiovascular birth defects.

Extrapolating from animal studies to human pregnancy, our studies showed that folate (FA) deficiency as well as one-time exposure to environmental factors in the first two to three weeks of human gestation can result in severe congenital heart defects (CHDs). Considering that approximately 49% of pregnancies are unplanned, this period of pregnancy can be considered high-risk for cardiac, as well as for neural, birth defects, as the woman usually is not aware of her pregnancy and may not yet be taking precautionary actions to protect the developing embryo. Using avian and mouse vertebrate models, we demonstrated that FA supplementation prevents CHD induced by alcohol, lithium, or elevation of the metabolite homocysteine, a marker for FA deficiency.

Effects of alcohol, lithium, and homocysteine on nonmuscle myosin-II in the mouse placenta and human trophoblasts.

Objective: Mouse embryonic exposure to alcohol, lithium, and homocysteine results in intrauterine growth restriction (IUGR) and cardiac defects. Our present study focused on the placental effects. We analyzed the hypothesis that expression of nonmuscle myosin (NMM)-II isoforms involved in cell motility, mechanosensing, and extracellular matrix assembly are altered by the 3 factors in human trophoblast (HTR8/SVneo) cells in vitro and in the mouse placenta in vivo.

Blood flow dynamics of one cardiac cycle and relationship to mechanotransduction and trabeculation during heart looping.

Analyses of form-function relationships during heart looping are directly related to technological advances. Recent advances in four-dimensional optical coherence tomography (OCT) permit observations of cardiac dynamics at high-speed acquisition rates and high resolution. Real-time observation of the avian stage 13 looping heart reveals that interactions between the endocardial and myocardial compartments are more complex than previously depicted.

Folate protection from congenital heart defects linked with canonical Wnt signaling and epigenetics.

Purpose Of Review: Environmental factors, such as drugs, chemicals, or abnormal concentrations of natural metabolites, induce birth defects. Environmental effects on cardiogenesis have been little studied in contrast to neurogenesis. This review presents evidence on three environmental factors: alcohol, the drug lithium, and the metabolite homocysteine, impacting the Wnt/β-catenin pathway during cardiac development and folate protection.

Calcium channel blockade in embryonic cardiac progenitor cells disrupts normal cardiac cell differentiation.

We suggest that characterization of processes involved in differentiation of the pluripotential cardiac precursor cells in their embryonic environment will permit identifying pathways important for induction of diverse stem cells toward the cardiac phenotype. Phenotypic characteristics of cardiac cells are their contractile and electrical properties. The objective of the present study was to define whether calcium (Ca(++)) has a regulatory role in the pluripotential precursor cell population during commitment into cardiomyocytes.

Fetal alcohol syndrome: cardiac birth defects in mice and prevention with folate.

Objective: Alcohol (ethanol) consumption during pregnancy is linked to congenital heart defects that are associated with fetal alcohol syndrome. Recent reports have associated ethanol exposure with the Wnt/beta-catenin pathway. Therefore, we defined whether ethanol affects Wnt/beta-catenin signaling during cardiac cell specification.

Folate rescues lithium-, homocysteine- and Wnt3A-induced vertebrate cardiac anomalies.

Elevated plasma homocysteine (HCy), which results from folate (folic acid, FA) deficiency, and the mood-stabilizing drug lithium (Li) are both linked to the induction of human congenital heart and neural tube defects. We demonstrated previously that acute administration of Li to pregnant mice on embryonic day (E)6.75 induced cardiac valve defects by potentiating Wnt-beta-catenin signaling.

Cellular nonmuscle myosins NMHC-IIA and NMHC-IIB and vertebrate heart looping.

Flectin, a protein previously described to be expressed in a left-dominant manner in the embryonic chick heart during looping, is a member of the nonmuscle myosin II (NMHC-II) protein class. During looping, both NMHC-IIA and NMHC-IIB are expressed in the mouse heart on embryonic day 9.5.

Molecular effects of lithium exposure during mouse and chick gastrulation and subsequent valve dysmorphogenesis.

Background: Lithium (Li) has been associated with cardiac teratogenicity in the developing fetus. We took advantage of the association of therapeutic administration of Li with an increase in heart defects to gain insight into both normal and pathological heart and valve development with GSK-3 inhibition. The objective of this study was to define whether Li mimicry of canonical Wnt/beta-catenin signaling induces cardiac valve defects.

Tropomyosin expression and dynamics in developing avian embryonic muscles.

The expression of striated muscle proteins occurs early in the developing embryo in the somites and forming heart. A major component of the assembling myofibrils is the actin-binding protein tropomyosin. In vertebrates, there are four genes for tropomyosin (TM), each of which can be alternatively spliced.

Cells that express MyoD mRNA in the epiblast are stably committed to the skeletal muscle lineage.

The epiblast of the chick embryo contains cells that express MyoD mRNA but not MyoD protein. We investigated whether MyoD-positive (MyoDpos) epiblast cells are stably committed to the skeletal muscle lineage or whether their fate can be altered in different environments. A small number of MyoDpos epiblast cells were tracked into the heart and nervous system.

A role for the cytoskeleton in heart looping.

Over the past 10 years, key genes involved in specification of left-right laterality pathways in the embryo have been defined. The read-out for misexpression of laterality genes is usually the direction of heart looping. The question of how dextral looping direction occurred mechanistically and how the heart tube bends remains unknown.

Early temporal-specific responses and differential sensitivity to lithium and Wnt-3A exposure during heart development.

Members of both Wnt and bone morphogenetic protein (BMP) families of signaling molecules are important in heart development. We previously demonstrated that beta-catenin, a key downstream intermediary of the canonical Wnt signaling pathway, delineates the dorsal boundary of the cardiac compartments in an anteroposterior progression. We hypothesized the progression involves canonical Wnt signaling and reflects development of the primary body axis of the embryo.

MCT-4, A511/Basigin and EF5 expression patterns during early chick cardiomyogenesis indicate cardiac cell differentiation occurs in a hypoxic environment.

We have identified the presence of the hypoxia marker EF5 in the stage 4/5 chick heart fields. This suggests that cardiac cell differentiation occurs in a relatively anaerobic environment. Monocarboxylate transporter (MCT) studies in adult cardiac myocytes have demonstrated that MCTs catalyze proton-linked pyruvate and lactate transport activity.

Cross talk between cell-cell and cell-matrix adhesion signaling pathways during heart organogenesis: implications for cardiac birth defects.

The anterior-posterior and dorsal-ventral progression of heart organogenesis is well illustrated by the patterning and activity of two members of different families of cell adhesion molecules: the calcium-dependent cadherins, specifically N-cadherin, and the extracellular matrix glycoproteins, fibronectin. N-cadherin by its binding to the intracellular molecule beta-catenin and fibronectin by its binding to integrins at focal adhesion sites, are involved in regulation of gene expression by their association with the cytoskeleton and through signal transduction pathways. The ventral precardiac mesoderm cells epithelialize and become stably committed by the activation of these cell-matrix and intracellular signaling transduction pathways.

Cardiac morphogenesis: matrix metalloproteinase coordination of cellular mechanisms underlying heart tube formation and directionality of looping.

During heart organogenesis, the spatiotemporal organization of the extracellular matrix (ECM) undergoes significant remodeling. Because matrix metalloproteinases (MMPs) are known to be key regulators of cell-matrix interactions, we analyzed the role(s) of MMPs, and specifically MMP-2, in early heart development. Both MMP-2 neutralizing antibody and the broad-spectrum MMP inhibitor Ilomastat in a temporal manner, when applied between chick embryonic stages 5 (primitive streak stage) to stage 12 ( approximately 16-somites), produced severe heart tube defects.

Effects of antisense misexpression of CFC on downstream flectin protein expression during heart looping.

Dextral looping of the heart is regulated on multiple levels. In humans, mutations of the genes CFC and Pitx2/RIEG result in laterality-associated cardiac anomalies. In animal models, a common read-out after the misexpression of laterality genes is heart looping direction.

Regulation of heart morphology: current molecular and cellular perspectives on the coordinated emergence of cardiac form and function.

Background: During early heart development, in addition to cells being induced to differentiate into cardiomyocytes, pathways are activated that lead to cardiac morphogenesis or the development of form.

Methods: Orchestration of organogenesis involves the incremental activation of regulatory pathways that lead to pivotal transition points, such as cardiac compartment delineation and looping. Each embryonic stage sets up the correct patterning of morphoregulatory molecules that will regulate the next process, until an organ is formed from the mesoderm layer after gastrulation.