Molecular actors of the Calcium signaling in the endothelial-to-mesenchymal transition: poorly explored therapeutic targets

Endothelial-to-mesenchymal transition (EndMT) is a cell trans-differentiation process which occurs during embryonic development as well as in a variety of pathological contexts. During this process, cells lose their endothelial lineage markers and gain mesenchymal ones. It is stimulated by several factors, such as TGF-β, high glucose, or hypoxia, which trigger intracellular pathways, mainly the Smad and ERK pathways, leading to modulation of transcription factors. While Ca 2+ signaling is known to participate in a wide variety of cellular processes, its role in the context of EndMT is only partially understood, although several Ca 2+ -carrying and Ca 2+ -regulated proteins have been shown to influence EndMT. These include Ca 2+ -permeable channels from the mechanosensitive Piezo family and members of the TRP family; the actors involved in store-operated Ca 2+ entry, including IP 3 -receptors located on the endoplasmic reticulum membrane, the endoplasmic reticulum Ca 2+ sensor STIM1, and the Ca 2+ -permeable plasma membrane channel Orai1; the mitochondrial Ca 2+ uniporter complex; Ca 2+ -activated channels such as the non-selective monovalent cation channel TRPM4 and the big-conductance K + channel BK Ca ; Ca 2+ -regulated signaling pathways such as the Ca 2+ -calmodulin-calcineurin-NFAT pathway and the calpain-ERK pathway. After a brief description of Ca 2+ signaling in endothelial cells, this review will specifically detail the available data on the Ca 2+ signaling in EndMT. Links between Ca 2+ signaling and other signaling pathways leading to EndMT will be discussed. Finally, molecular targets that may be valuable to explore in order to prevent EndMT will be highlighted.