Endothelial to mesenchymal transition: at the axis of cardiovascular health and disease

The vascular endothelium is a major regulator of vessel biology in health and disease. While the importance of the endothelium has long been recognized to be at the axis of health and disease,¹ important breakthroughs have been made over the last decades.^2–5 Recent studies demonstrate that endothelial cells (ECs) show great plasticity and heterogeneity, as underscored by their highly specialized functions across different organs and vascular beds.^6,7 Activated ECs have the capacity to undergo endothelial-to-mesenchymal transition (EndMT), a complex biological process defined by the progressive and dynamic loss of endothelial phenotype concurrent with the acquisition of a mesenchymal profile.^8–11 EndMT is fundamental for atrioventricular (AV) valve formation in developmental cardiogenesis and is widely recognized to promote cellular trans-differentiation or transient cellular adaptions.^12–14 A wide body of research has demonstrated that EndMT is associated with divergent pathologies including malignancy, vascular, inflammatory, and fibrotic diseases,^15–21 as summarized in Figure 1. The precise molecular mechanisms governing EndMT remain, in the main, elusive, particularly in the context of EC fate and transitioning spectrum, the identity of downstream EndMT-derived cell subtypes, process remodelling, and reversal. In this review, the endothelial-to-mesenchymal phenotypic switch will be described both in contexts of cardiovascular development and (patho)-physiological remodelling. We then discuss key signalling pathways, epigenetic mechanisms, and EndMT-associated transcriptional factors (TFs) implicated in such contexts. Additionally, current limitations in EndMT experimental models and in high-throughput techniques are discussed while proposing advances that can reinforce future studies. Despite prevailing limitations, the advancement in the study of EndMT and its biology hold the promise of being new therapeutic avenues in human disease.