Endothelial to mesenchymal transition in cardiovascular diseases: molecular insights and clinical perspectives

Abstract Endothelial to mesenchymal transition (EndMT) is a process whereby endothelial cells transition to adopt a mesenchymal-like fate, e.g. to become smooth muscle cells, osteoblasts, fibroblasts, or chondrocytes. In embryonic heart development, the importance of EndMT was established several decades ago, with ECs undergoing EndMT to give rise to the endocardial cushions that ultimately develop into the cardiac valves. More recently, EndMT has been observed in various adult cardiovascular diseases. This has been established through the application of state-of-the-art research tools, including cell lineage tracing in mice and single cell RNA sequencing, which have allowed in depth profiling of endothelial cells that have undergone transition to a mesenchymal-like state. As with any emerging field, certain challenges have arisen, such as the lack of a standardized definition of what constitutes EndMT at a molecular level and obtaining proof in humans that EndMT is mechanistically involved in the pathophysiology of cardiovascular diseases. The greatest evidence for the presence of cells undergoing EndMT in the adult exists for transplant vasculopathy, pulmonary arterial hypertension, vein graft remodeling, atherosclerosis, and valvular heart disease. The transforming growth factor beta pathway is the major driver, but this is not the exclusive signalling mechanism governing this complex process. Translational large animal studies have already been undertaken to inhibit EndMT in both valvular heart disease and vein graft remodeling, with positive results. These studies pave the way towards first-in-human clinical inhibition of EndMT as a therapeutic strategy. Here we review this exciting field, with particular emphasis on the functional role of EndMT in adult cardiovascular diseases using atherosclerosis and valvular disease as exemplars.