A new study from the German Cancer Research Center (DKFZ) and the Mannheim Medical Faculty of Heidelberg University reveals a critical epigenetic mechanism controlling the development of blood vessels in the mouse placenta. The research highlights the role of DNA methylation in placental vascular formation and connects deficiencies in this process to pregnancy complications such as fetal growth retardation and preeclampsia.
Background:
The placenta, a vital organ during pregnancy, facilitates the exchange of oxygen, nutrients, and waste between the mother and fetus. Proper placental blood vessel development is essential for this exchange. However, when blood vessel growth is impaired, a condition called placental insufficiency can arise, leading to fetal growth retardation, a known pregnancy complication.
Vascular specialist Hellmut Augustin, who led the research, emphasized that abnormal blood vessel development in the placenta is one of the primary causes of fetal growth problems. To understand the underlying mechanisms of these vascular malformations, the research team examined mouse placental blood vessels at the single-cell level, focusing on endothelial cells, which play a central role in the formation of blood vessels.
Epigenetic Control of Placental Blood Vessel Development:
The research uncovered a crucial epigenetic mechanism that regulates gene expression in placental endothelial cells. The researchers observed that in the normal development of the placenta, gene activity in the endothelial cells decreased from the maternal side of the placenta to the fetal side, forming a distinct zonation pattern. This pattern was linked to the strength of blood flow within the placenta.
Epigenetic modifications, specifically DNA methylation, were found to regulate this zonation. DNA methylation involves adding methyl groups to DNA, affecting gene activity. The researchers focused on DNA methyltransferases, enzymes that modify DNA methylation patterns. They identified DNMT3A, a methyltransferase enzyme, as a key player in regulating DNA methylation in the fetal placental endothelium.
When DNMT3A was genetically deleted in mice, DNA methylation in the endothelial cells was reduced, and the normal zonation of gene expression was lost. This disruption in DNA methylation led to impaired placental blood vessel development and fetal growth retardation, which persisted even after birth.
Connection to Pregnancy Complications:
To validate the findings from the mouse model, the research team compared gene expression data from endothelial cells of healthy human placentas with those from women suffering from preeclampsia, a pregnancy complication that impairs placental blood supply and leads to growth problems in the fetus. The researchers found that, similar to the mouse model, placental endothelial cells in preeclampsia patients exhibited reduced DNMT3A expression.
This correlation between mouse data and human patient data strengthens the conclusion that DNMT3A plays a pivotal role in the healthy development of placental blood vessels. A deficiency in this enzyme could contribute significantly to conditions like preeclampsia and placental insufficiency.
Conclusion:
This study provides new insights into the role of epigenetic mechanisms, particularly DNA methylation, in placental blood vessel development. Understanding how DNMT3A regulates placental endothelial gene expression offers promising directions for further research into pregnancy disorders and the development of targeted treatments for conditions like preeclampsia. The findings also highlight the importance of epigenetic regulation in ensuring the proper functioning of the placenta and fetal development.
The results of this study, published by Stephanie Gehrs and her colleagues, lay the groundwork for future investigations into how epigenetic mechanisms might be leveraged to better understand and potentially treat pregnancy-related vascular disorders.
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