Ve-cadherin-mediated Epigenetic Regulation Of Endothelial Gene Expression
VEC and its partners play pivotal roles in the epigenetic regulation of endothelium. VEC expression regulates endothelial gene expression by repressing the FoxO1/b-catenin complex. VEC also binds to the promoter of genes related to endothelial stability, such as claudin-5. In addition, VEC inhibits the binding of polycomb proteins to the gene promoter.
It is important to note that ECs undergo epigenetic regulation in response to oxidative stress. ROS and hypoxia alter DNA methylation, which affects EC function. Alterations in DNA methylation may lead to alterations in phenotype and function of endothelial cells, and disrupt vascular homeostasis.
This epigenetic regulation involves a complex of proteins, which bind to chromatin, including PcG proteins. PcG proteins inhibit gene expression by physically associating with promoters, thereby causing chromatin conformational changes and gene inhibition. Other proteins, including b-catenin, stabilize PcG protein binding to DNA.
While the majority of the research on m6A has been conducted in cardiomyocytes, it is likely that EC expression is also regulated by changes in m6A. Hypoxia has been identified as a key stimulus for changes in m6A, including in other types of cells. Hypoxia, for example, has been implicated in changes in m6A in NANOG and breast cancer stem cells. However, HUVECs have not been studied under hypoxia for 16 hours.
Interestingly, VE-cadherin levels in the blood of JIA patients were significantly higher than those in the healthy controls. In addition, the presence of a soluble fraction of VE-cadherin in JIA patients was associated with significantly higher VE-cadherin expression.
The complex mechanisms regulating vascular maturation are poorly understood. A number of human diseases have been associated with abnormal angiogenesis. For example, solid tumors are fueled by newly formed, structurally abnormal vessels with wide interendothelial junctions. In these cells, VEC is the dominant adhesion junction protein. This protein triggers the expression of genes associated with endothelial differentiation.
VEC clustering triggers a series of epigenetic events and pathways that regulate several aspects of endothelial homeostasis. A comparison between VEC-null and VEC-positive cells suggests a general role of VEC in activating endothelial genes. The results also demonstrate that VEC plays a major role in vascular stability-related gene expression. In addition, reduced expression of VEC was accompanied by decreased levels of claudin-5 and VEPTP, two important endothelial proteins.
ECs are essential in the heart, and the epigenetic control of endothelial gene expression is an important part of regulating the heart’s heart function. Several groups have demonstrated that the regulation of gene expression by DNA methylation may improve the efficiency of EC differentiation. Further, DNA methylation is altered in ECs during hypoxia, hyperglycemia, and ageing.
Despite the importance of ECs in the development and maintenance of cardiovascular homeostasis, these findings have not provided a clear picture of how alterations in DNA methylation in these cells affect their function. Nevertheless, further studies are needed to determine whether DNA methylation alters the expression of gene-related genes in heart cells. If this is the case, these findings may provide novel targets for therapeutic intervention in HF.