Endothelial‐to‐mesenchymal transition in cardiovascular diseases: Developmental signaling pathways gone awry

Abstract

The process named endothelial-to-mesenchymal transition (EndMT) was observed for the first time during the development of the chicken embryo several decades ago. Of interest, accumulating evidence suggests that EndMT plays a critical role in the onset and progression of multiple postnatal cardiovascular diseases. EndMT is controlled by a set of developmental signaling pathways, very similar to the process of epithelial-to-mesenchymal transition, which determine the activity of several EndMT transcriptional effectors. Once activated, these EndMT effectors regulate the expression of endothelial-and mesenchymalspecific genes, in part by interacting with specific motifs in promoter regions, eventually leading to the down-regulation of endothelial-specific features and acquisition of a fibroblast-like phenotype. Important technical advances in lineage tracing methods combined with experimental mouse models demonstrated the pathophysiological importance of EndMT for human diseases. In this review, we discuss the major signal transduction pathways involved in the activation and regulation of the EndMT program. Furthermore, we will review the latest discoveries on EndMT, focusing on cardiovascular diseases, and in particular on its role in vascular calcification, pulmonary arterial hypertension, and organ fibrosis. Developmental Dynamics 247:492-508,

Development of Macrocycle Kinase Inhibitors for ALK2 Using Fibrodysplasia Ossificans Progressiva‐Derived Endothelial Cells

“…(13) Endothelial cells overexpressing the FOP mutant ALK2 receptor are prone to undergo EndMT in response to TGF‐β and BMP ligands . In addition, EndMT has been unveiled as a key phenomenon for proper cardiovascular development and evidence for its contribution to the onset and progression of postnatal cardiovascular disease is accumulating . To investigate whether FOP ECFCs may be sensitized to undergo EndMT and become fibroblast‐like cells, we performed immunofluorescent labeling (Fig.…”

Foxc2 is required for proper cardiac neural crest cell migration, outflow tract septation, and ventricle expansion

“…The lack of pharyngeal Plxnd1 expression in Foxc2 ‐/‐ embryos was not due to an absence of post‐otic or pharyngeal arch mesenchyme or vasculature as evidenced by the expression of Twist1 (Sanchez‐Duffhues et al, ) (Fig. E,F) and PECAM1 (Fig.…”

Myostatin promotes the epithelial‐to‐mesenchymal transition of the dermomyotome during somitogenesis

“…Finally, A549 and MDCK cells treated with MSTN in vitro showed morphological changes consistent with EMT, shifting from cuboidal to elongated spindle shapes. It is well known that the loss of epithelial markers and the acquisition of mesenchymal features occur through a well‐orchestrated transcription program that involves the Snail, ZEB, and basic helix–loop–helix families of transcription factors (Thiery et al, ; Xu et al, ; Sanchez‐Duffhues et al, ). In the present work, A549 cells and MDCK cells treated with MSTN showed clear expressional increases in members of these transcription factor families.…”

“…It is well known that most members of the TGF-β superfamily activate multiple signaling pathways and are widely involved in diverse developmental and physiological processes (Sanchez-Duffhues et al, 2018;Santibanez et al, 2018). After binding to its receptors and forming receptor complexes, MSTN activates the Smad 2/3/4 complex and regulates the expression levels of its target genes, including MyoD and those encoding other myogenic regulatory factors (Lee and McPherron, 2001).…”