Hypermethylation of the Bmp4 promoter dampens binding of HIF-1α and impairs its cardiac protective effects from oxidative stress in prenatally GC-exposed offspring.

The exposure to an unhealthy environment in utero can lead to the occurrence of cardiovascular diseases in the offspring. Glucocorticoids (GC) are essential for normal development and maturation of fetal organs and is a first-line treatment for pregnant women affected by autoimmune diseases. However, excess prenatal GC exposure might program the development of fetal organs and cause a number of chronic diseases in later life. Our previous studies indicated that cardiac functions were significantly compromised in rat offspring prenatally exposed to the synthetic glucocorticoid dexamethasone (DEX), only after ischemia-reperfusion. In the present study, we further observed that DNA hypermethylation of bone morphogenetic protein 4 (Bmp4) promoter in cardiomyocytes caused by prenatal DEX exposure substantially dampened the binding activity of transcription factor HIF-1α induced by cardiac ischemia. Therefore, prenatal DEX exposure inhibits the induction of BMP4 upon I/R and attenuates the protective effects of BMP4 in cardiomyocytes, which eventually manifests as malfunction of the adult heart. Moreover, we employed two cardiac-specific Bmp4 knock-in mouse models and found that in vivo BMP4 overexpression could rescue the cardiac dysfunction caused by prenatal GC exposure. In depth mechanistic research revealed that BMP4 protects the cardiomyocytes from mitophagy and apoptosis by attenuating mitochondrial PGC-1α expression in a p-Smad and Parkin-dependent manner. These findings suggest that prenatal GC exposure increases the susceptibility of the offspring's heart to a "second strike" after birth, due to the failure of hypoxia-induced HIF-1α transactivation of the hypermethylated Bmp4 promoter in cardiomyocytes. Pretreatment with the DNA methylation inhibitor, 5-Aza-2'-deoxycytidine, could be a potential therapeutic method for this programming effect of GC exposure during pregnancy on neonatal cardiac dysfunction.

[Placental mechanisms underlying the effects of maternal stress on the fetal development].

Placenta is the only link between the pregnant woman and fetus, and the basis for maintaining the normal pregnancy process and fetal development. Maternal stress is the maternal physiological and psychological changes caused by various factors, characterized by the increased level of glucocorticoid, which affects the hypothalamic-pituitary-target gland axis and regulates the expression of target genes. Maternal stress also changes the weight, metabolism and nutrient transportation of the placenta, which will substantially influence the development of fetus. This paper will firstly summarize the characteristics of maternal stress and its influence on offspring. Then, the changes in the body under maternal stress will be described. Finally, we will clarify the proven mechanisms underlying maternal stress and raise some important problems that have not been clarified in this area. The study of maternal stress on fetus and its underlying mechanisms will serve as theoretical basis for the diagnosis and treatment of the stress-related pregnant diseases and disorders.

Decrease in SHP-1 enhances myometrium remodeling via FAK activation leading to labor.

Preterm birth is one of the most common complications during human pregnancy and is associated with a dramatic switch within the uterus from quiescence to contractility. However, the mechanisms underlying uterine remodeling are largely unknown. Protein kinases and phosphatases play critical roles in regulating the phosphorylation of proteins involved in the smooth muscle cell functions. In the present study, we found that Src-homology phosphatase type-1 (SHP-1, PTPN6) was significantly decreased in human myometrium in labor compared with that not in labor. Timed-pregnant mice injected intraperitoneally with the specific SHP-1 inhibitor protein tyrosine phosphatase inhibitor I (PTPI-1) manifested significantly preterm labor, with enriched plasmalemmal dense plaques between myometrial cells and increased phosphorylation at Tyr397 and Tyr576/577 sites of focal adhesion kinase (FAK) in myometrial cells, which remained to the time of labor, whereas the phosphorylation levels of ERK1/2 and phosphatidylinositol 3 kinase (PI3K) showed a rapid increase upon PTPI-1 injection but fell back to normal at the time of labor. The Tyr576/577 in FAK played an important role in the interaction between FAK and SHP-1. Knockdown of SHP-1 dramatically increased the spontaneous contraction of human uterine smooth muscle cells (HUSMCs), which was reversed by coinfection of a FAK-knockdown lentivirus. PGF2α downregulated SHP-1 via PLCß-PKC-NF-κB or PI3K-NF-κB pathways, suggesting the regenerative downregulation of SHP-1 enhances the uterine remodeling and plasticity by activating FAK and subsequent focal adhesion pathway, which eventually facilitates myometrium contraction and leads to labor. The study sheds new light on understanding of mechanisms that underlie the initiation of labor, and interventions for modulation of SHP-1 may provide a potential strategy for preventing preterm birth.

The detrimental effects of glucocorticoids exposure during pregnancy on offspring's cardiac functions mediated by hypermethylation of bone morphogenetic protein-4.

The intra-uterine and external environmental factors not only affect the early development of fetuses, their interaction with genesis will also substantially program the physiological functions of offspring throughout life. Synthetic glucocorticoid (GC) is widely used for the management of women at risk of preterm birth or undergone autoimmune diseases. However, excess GC might cause a number of chronic diseases in later life. In the present study, we set up a programming rat model by daily injection of dexamethasone (DEX) since 14.5 dpc until labor, and found that the cardiac functions were significantly compromised in the male offspring compared with that exposed to NS, especially after ischemia/reperfusion (I/R), due to the increased infarction and apoptosis of myocardium. Using MeDIP sequencing, we identified four genes involved in the cardiac muscle cell differentiation and development pathway exhibited increased methylation in their promoter regions, among which, bone morphogenetic protein-4 (BMP4) expression is coordinately decreased in myocardium from male mice prenatally exposed to DEX. The programming effect of DEX on cardiomyocytes apoptosis was found to be dependent on mitochondria dysfunction, whereas the breakdown of mitochondrial membrane potential (ΔΨm) and the decrease of ATP production from mitochondria caused by prenatal DEX exposure both can be restored by BMP4 predisposing on neonatal cardiomyocytes 24 h prior to I/R. Inversely consistent with ΔΨm and ATP production, the release of reactive oxygen species was dramatically elevated in cardiomyocytes, which was significantly inhibited in the presence of BMP4 prior to I/R. These findings suggested that the excess GC exposure during pregnancy increases the susceptibility of male offspring's heart to "second strike", due to the decrease of BMP4 expression caused by the hypermethylation on Bmp4 promoter and the absence of BMP4 protective effect in cardiomyocytes, making the addition of BMP4 a promising treatment for the congenital heart disease under such circumstances.