The Role of Endothelial-to-Mesenchymal Transition in Cardiovascular Disease

Abstract

Endothelial-to-mesenchymal transition (EndoMT) is the process of endothelial cells progressively losing endothelial-specific markers and gaining mesenchymal phenotypes. In the normal physiological condition, EndoMT plays a fundamental role in forming the cardiac valves of the developing heart. However, EndoMT contributes to the development of various cardiovascular diseases (CVD), such as atherosclerosis, valve diseases, fibrosis, and pulmonary arterial hypertension (PAH). Therefore, a deeper understanding of the cellular and molecular mechanisms underlying EndoMT in CVD should provide urgently needed insights into reversing this condition. This review summarizes a 30-year span of relevant literature, delineating the EndoMT process in particular, key signaling pathways, and the underlying regulatory networks involved in CVD.

Shear Stress Initiates Endothelial to Mesenchymal Transition in Endocardial Endothelial Cells

“…During this process, the endothelial cells lose their endothelial characteristics, and begin to express mesenchymal markers (13,14,16,17,21). The transition is a continuum, and endothelial cells undergoing EndMT co-express both endothelial and mesenchymal markers (13,18,19). While there are hallmarks of early and late EndMT, studies have shown this can vary depending on the pathological environment and cell type (14)(15)(16)18,19).…”

“…While there are hallmarks of early and late EndMT, studies have shown this can vary depending on the pathological environment and cell type (14)(15)(16)18,19). Additionally, cells can undergo partial or full EndMT transition, further complicating detection of EndMT transition (13,18,19). An important regulator of EndMT is Snail1, a transcription factor known to induce EndMT (13,22,17,19,20,(23)(24)(25)(26).…”

“…We looked to the literature to investigate how these signaling markers could be linked, and we found that upregulation of gene expression for these markers are indicative of endothelial-to-mesenchymal transition (EndMT). During EndMT, endothelial cells that are exposed to specific developmental programming stimuli or pathological conditions undergo a transition to a mesenchymal phenotype, such as fibroblasts or smooth muscle cells (13–19). EndMT is a transition process, therefore cells undergoing EndMT can exhibit markers of both endothelial and mesenchymal cells at once (13,14,19,20).…”

“…During EndMT, endothelial cells that are exposed to specific developmental programming stimuli or pathological conditions undergo a transition to a mesenchymal phenotype, such as fibroblasts or smooth muscle cells (13–19). EndMT is a transition process, therefore cells undergoing EndMT can exhibit markers of both endothelial and mesenchymal cells at once (13,14,19,20). To detect early EndMT, one would look for an upregulation of mesenchymal genes and the proteins they encode for, such as α-smooth muscle actin protein (encoded by ACTA2 ), CD44 protein (encoded by CD44 ), and Snail1 protein (encoded by SNAI1 ), and a downregulation of endothelial genes and the proteins they encode for, such as von Willebrand Factor protein (encoded by VWF ), CD31 protein (encoded by CD31 ), and VE cadherin protein (encoded by CDH5 ) (13–15,18,19).…”

“…EndMT is a transition process, therefore cells undergoing EndMT can exhibit markers of both endothelial and mesenchymal cells at once (13,14,19,20). To detect early EndMT, one would look for an upregulation of mesenchymal genes and the proteins they encode for, such as 𝛼𝛼- (encoded by MMP2 and MMP9, respectively), and a downregulation of endothelial genes and the proteins they encode for, such as CD31 and von Willebrand Factor (13)(14)(15)18,19).…”