Abstract
Endothelial-mesenchymal transition (EndMT) drives endothelium to contribute to normal development and disease processes. Here, we report that EndMTs occur in the diabetic endothelium of Ins2Akita/wt mouse, and show that induction of sex determining region Y-box 2 (Sox2) is a mediator of excess BMP signaling that results in activation of EndMTs and increased vascular calcification. We also find an induction of a complex of serine proteases in the diabetic endothelium, required for the up-regulation of Sox2. Our results suggest that EndMTs contribute to vascular calcification in diabetic arteries.
Highlights
Endothelial-mesenchymal transition (EndMT) is a process through which endothelial cells (ECs) transit into mesenchymal stem cells and gain plasticity for non-EC lineages [1, 2]
To determine whether ECs undergo EndMTs as part of this process, we examined the aortic endothelium of Ins2Akita/+ mice at 40 weeks of age, when calcified lesions can be detected in the aortas [11, 14]
Using Transmission electron microscopy (TEM) and scanning electron microscopy (SEM), we observed that the internal elastic lamina (IEL), which is in close contact with endothelium, was degraded in the diabetic aortas (Fig 1a, top)
Summary
Endothelial-mesenchymal transition (EndMT) is a process through which endothelial cells (ECs) transit into mesenchymal stem cells and gain plasticity for non-EC lineages [1, 2]. We showed that EndMTs drive endothelium to a mesenchymal state and directly contribute cells to the calcifying process in MGP-deficient aortas. These studies support EndMTs as a novel mechanism of EC contributing to vascular calcification [13]. We demonstrated the presence of cells with EC-origin in calcified lesions in diabetic aortas by lineage tracing [14, 16], suggesting that diabetic endothelium produces osteoinductive factors, but directly contributes cells to the calcifying process. EndMT in Vascular Calcification of Diabetes Mellitus limited by enhanced BMP inhibition [16] It is still unclear how the ECs gain plasticity to undergo osteogenesis in the setting of high glucose. The results suggest that EndMTs contribute to vascular calcification in diabetes mellitus
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