Atrioventricular valve abnormalities: From molecular mechanisms underlying morphogenesis to clinical perspective

Abstract

Malformation of the atrioventricular (AV) cushion is a common congenital heart defect. Ebstein’s anomaly, characterized by a heart defect related to the AV cushion, involves not only a valve defect but also a myocardial abnormality such as Uhl’s anomaly. The morphogenetic features of the heart in the case of these diseases can be used as a reference for investigating valvuloseptal and myocardial formations in the human heart. The AV endocardium transforms into the cushion mesenchyme through epithelial-mesenchymal transition (EMT). After the EMT, distal outgrowth and maturation of endocardial cushions are important morphogenetic steps for AV valvuloseptal morphogenesis. While bone morphogenetic protein (BMP)- 2 is known to be critical for AV EMT, little is known about the functional relationship between BMP and ECM and their roles in cushion mesenchymal cell (CMC) migration after EMT. In our previous study, we showed that BMP-2 and BMP signaling induced AV CMC migration. We have been exploring the role of BMP-2 in the regulation of valvulogenic extracellular matrix (ECM) components, periostin, versican, and hyaluronic acid (HA), and cell migration during post-EMT AV cushion expansion and maturation. We further examined whether BMP-2-promoted cell migration is associated with expression of periostin, versican, and HA. BMP-2-promoted cell migration is significantly impaired by treatment with versican siRNA and HA oligomer. We also found that transcription of Twist and Id1, implicated in cell migration in embryogenesis and activation of the periostin promoter, was induced by BMP-2 but repressed by noggin in CMC cultures. Taken together, we provide evidence that BMP-2 induces expression and deposition of three major ECM proteins, periostin, versican, and HA, and that these ECM components contribute to BMP-2-induced CMC migration during post-EMT AV cushion expansion and maturation. Based on these findings, we discuss the morphogenetic process of AV valve abnormalities and crosstalk between valve and cardiomyocytes morphogenesis.