Reassessing endothelial-to-mesenchymal transition in cardiovascular diseases

Abstract

Endothelial cells and mesenchymal cells are two different cell types with distinct morphologies, phenotypes, functions, and gene profiles. Accumulating evidence, notably from lineage-tracing studies, indicates that the two cell types convert into each other during cardiovascular development and pathogenesis. During heart development, endothelial cells transdifferentiate into mesenchymal cells in the endocardial cushion through endothelial-to-mesenchymal transition (EndoMT), a process that is critical for the formation of cardiac valves. Studies have also reported that EndoMT contributes to the development of various cardiovascular diseases, including myocardial infarction, cardiac fibrosis, valve calcification, endocardial elastofibrosis, atherosclerosis, and pulmonary arterial hypertension. Conversely, cardiac fibroblasts can transdifferentiate into endothelial cells and contribute to neovascularization after cardiac injury. However, progress in genetic lineage tracing has challenged the role of EndoMT, or its reversed programme, in the development of cardiovascular diseases. In this Review, we discuss the caveats of using genetic lineage-tracing technology to investigate cell-lineage conversion; we also reassess the role of EndoMT in cardiovascular development and diseases and elaborate on the molecular signals that orchestrate EndoMT in pathophysiological processes. Understanding the role and mechanisms of EndoMT in diseases will unravel the therapeutic potential of targeting this process and will provide a new paradigm for the development of regenerative medicine to treat cardiovascular diseases.

Human Peripheral Blood-Derived Endothelial Colony-Forming Cells Are Highly Similar to Mature Vascular Endothelial Cells yet Demonstrate a Transitional Transcriptomic Signature

“…Co-culture of ECFC with mesenchymal stromal cells significantly alters their gene expression program (≈ 1700 DEGs) triggering endothelial-to-mesenchymal transition, potentially through elevated expression of SNAI1 and SNAI2 genes [45] encoding, respectively, transcription factors Snail and Slug, master regulators of this process [46][47][48]. Interestingly, in our study, SNAI1 was upregulated whilst SNAI2 was downregulated in ECFC compared with SAT-SVF, probably reflecting different stages of endothelial differentiation.…”

Endothelial Cell Mechanotransduction in the Dynamic Vascular Environment

“…[124] Together, these studies suggest involvement of EndMT in linking disturbed flow to inflammation and atherogenesis. [125] …”

“…Novel strategies for in-vitro recapitulation of EndMT, real time imaging of population transition dynamics, and studies of functional changes such as gain of contractile ability or loss of monocyte adhesiveness in addition to expression of cell markers may help to dissect the molecular mechanisms responsible for endothelial plasticity as well as the critical roles of mechanical stimuli. [125] …”

Endothelial cell–cardiomyocyte crosstalk in heart development and disease

“…On the other hand, under hypoxic conditions cardiac ECs release transforming growth factor β, which in turn promotes endothelial to mesenchymal transition (EndoMT) in an autocrine loop, but also induces apoptosis in CMs (Sniegon et al 2017). While several studies have reported that EndoMT contributes to the development of cardiac fibrosis after ischaemia or in other pathological settings (Xu et al 2016), recent progresses in genetic lineage tracing has challenged its role in vivo after cardiac injury (Li et al 2018), warranting further studies to confirm the extent and function of EndoMT after cardiac ischaemia.…”