The regulation of endothelial-to-mesenchymal transition in endocardial cushion development: Signaling pathways and transcription factors.

Endocardial cushions, derived from the atrioventricular canal (AVC) and outflow tract (OFT), serve as the primordia for the formation of the septum and valves. Improper morphogenesis of the endocardial cushion leads to septal and valvular abnormalities, which contribute to the largest proportion of congenital heart diseases (CHDs). The development and maturation of the endocardial cushion rely on endothelial-to-mesenchymal transition (EndMT), a process by which endocardial cells undergo morphological remodeling and develop into the endocardial cushion mesenchyme. This biological event is strictly governed by regional signals originating from the myocardium, endocardium, and mesenchyme. Various signaling pathways, including TGFβ/BMP, Wnt, Notch, Hippo/YAP, PI3K/AKT, VEGF, and mechanical stress, are involved in the modulation of endocardial cell proliferation, migration, and mesenchymal transition. Transcription factors, such as SMAD, SNAIL, TWIST, TBX2, SOX9, KLF2/4, and NFATc1, exert distinct effects on endocardial EndMT. Maternal environmental exposures can disrupt signaling pathways and transcriptional network during endocardial cushion development, thereby enhancing susceptibility to CHDs. This review summarizes the mechanistic pathways and transcriptional regulation in AVC endocardial cushion development and EndMT, highlighting their association with CHDs.