TGFβ and Wnt in Cardiac Outflow Tract Defects in Offspring of Diabetic Pregnancies

Abstract

Background Diabetes mellitus in pregnancy causes defects in infant heart, includingthe outflow tracts (OFTs). Development of the aorta and pulmonary artery, which are derived from the common OFT in the embryo, is regulated by the transforming growth factor β (TGFβ) and Wnt families, and can be perturbed by hyperglycemia-generated intracellular stress conditions. However, the underlying cellular and molecular mechanisms remain to be delineated. Methods Female mice were induced diabetic with streptozotocin. Embryonic and fetal OFTs were examined morphologically and histologically. Cell proliferation was assessed using BrdU-incorporation assay. Oxidative and endoplasmic reticulum (ER) stresses and TGFβ factors were detected using immunohistochemistry. The expression of genes in the Wnt signaling system was assessed using real-time RT-PCR array. The role of Activin-A in cell proliferation was addressed by treating embryos cultured in high glucose with Activin-A. Results Maternal diabetes caused complex abnormalities in the OFT, including aortic and pulmonary stenosis and persistent truncus arteriosus. The development of the endocardial cushions was suppressed, manifested with insufficient cellularization of the tissues. Cell proliferation was significantly decreased under oxidative and ER stress conditions. The expression of genes in the Wnt signaling was significantly altered. Activin-A and Smad3 were found to be expressed in the OFT. Treatment with Activin-A rescued cell proliferation in the endocardial cushions. Conclusions Maternal diabetes generates oxidative and ER stress conditions, suppresses TGFβ and Wnt signaling, inhibits cell proliferation and cellularization of the endocardial cushions, leading to OFT septal defects. Activin-A plays a role in hyperglycemia-suppressed proliferation of the endocardial cells.

Sexual dimorphism in the fetal cardiac response to maternal nutrient restriction

“…Suppression of TGFβ signaling in fetal hearts has been previously reported in the mouse model of gestational diabetes [117]. Our observation might be explained by a mixed cell population of fibroblasts and cardiomyocytes in our samples.…”

Prevalence and Association of Congenital Anomalies According to the Maternal Body Mass Index: Cross-Sectional Study

“…47 In this case, inadequate metabolic monitoring during organogenesis is considered the main factor associated with the development of CAs. 45 The literature and our findings reinforce the importance of clarifying the severity of DM and its role in the alteration of obstetric parameters and in the development of CAs in fetuses of overweight and of obese pregnant women during prenatal visits. 48,49 The present study has some limitations.…”

“…It is hypothesized that hyperglycemia impairs the development of the vitelline sac and of the placenta through increased production and release of oxygen free radicals and inositol and arachidonic acid deficiency, which induce a reduction in placental communication between the pregnant woman and her fetus. 45,46 Uncontrolled hyperglycemia in the first weeks of gestation causes severe complications such as the risk of miscarriage and CAs, including atrial septal defect, anencephaly, sacral and adrenal agenesis. In the 2 nd trimester, maternal hyperglycemia causes exacerbated fetal growth and increased risk of fetal death during the last 4 to 6 weeks of gestation.…”

WNT signaling in atrial fibrillation

“…77 It is the inhibition of the Wnt pathway that seems to be responsible for the malformation of the heart caused by gestational diabetes. 78…”