Reassessing endothelial-to-mesenchymal transition in cardiovascular diseases

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.