Reconceptualizing Endothelial-to-mesenchymal transition in atherosclerosis: Signaling pathways and prospective targeting strategies

Background: The modification of endothelial cells (ECs) biological function under pathogenic conditions leads to the expression of mesenchymal stromal cells (MSCs) markers, defined as endothelial-to-mesenchymal transition (EndMT). Invisible in onset and slow in progression, atherosclerosis (AS) is a potential contributor to various atherosclerotic cardiovascular diseases (ASCVD). By triggering AS, EndMT, the "initiator" of AS, induces the progression of ASCVD such as coronary atherosclerotic heart disease (CHD) and ischemic cerebrovascular disease (ICD), with serious clinical complications such as myocardial infarction (MI) and stroke. In-depth research of the pathomechanisms of EndMT and identification of potential targeted therapeutic strategies hold considerable research value for the prevention and treatment of ASCVD-associated with delayed EndMT. Although previous studies have progressively unraveled the complexity of EndMT and its pathogenicity triggered by alterations in vascular microenvironmental factors, systematic descriptions of the most recent pathogenic roles of EndMT in the progression of AS, targeted therapeutic strategies, and their future research directions are scarce.

Aim of review: We aim to provide new researchers with comprehensive knowledge of EndMT in AS. We exhaustively review the latest research advancements in the field and provide a theoretical basis for investigating EndMT, a biological process with sophisticated mechanisms.

Key scientific concepts of review: This review summarized that altered hemodynamics with microenvironmental crosstalk consisting of inflammatory responses or glycolysis, oxidative stress, lactate or acetyl-CoA (Ac-CoA), fatty acid oxidation (FAO), intracellular iron overload, and transcription factors, including ELK1 and STAT3, modulate the EndMT and affect AS progression. In addition, we provide new paradigms for the development of promising therapeutic agents against these disease-causing processes and indicate promising directions and challenges that need to be addressed to elucidate the EndMT process.