Co-ordinating Notch, BMP, and TGF-β signaling during heart valve development

Abstract

Congenital heart defects affect approximately 1-5% of human newborns each year and of these cardiac defects, 20-30% are due to heart valve abnormalities. Recent literature indicates that key factors and pathways that regulate valve development are also implicated in congenital heart defects and valve disease. Currently, there are limited options for treatment of valve disease and therefore, having a better understanding of valve development can contribute critical insight into congenital valve defects and disease. There are three major signalling pathways required for early specification and initiation of Endothelial-to-Mesenchymal Transformation (EMT) in the cardiac cushions: BMP, TGFβ, and Notch signalling. BMPs secreted from the myocardium setup the environment for the overlying endocardium to become activated, Notch signalling initiates EMT, and both BMP and TGFβ signalling synergizes with Notch to promote the transition of endothelia to mesenchyme and to promote mesenchymal cell invasiveness. Together, these three essential signalling pathways help to form the cardiac cushions and populate them with mesenchyme and, consequently, set off the cascade of events required to develop mature heart valves. Furthermore, integration and cross-talk between these pathways generate highly stratified and delicate valve leaflets and septa of the heart. Here, we discuss BMP, TGFβ, and Notch signalling pathways during mouse cardiac cushion formation and how they together produce a coordinated EMT response in the developing mouse valves.

Vasa Vasorum in Normal and Diseased Arteries

“…82,83 This sequence of events occurs during normal embryonic development, in which EndMT plays a crucial role in formation of cardiac valves. [84][85][86] However, it also occurs in a number of pathological settings in adult tissues, including myocardial infarction, 83,87 fibrosis, [88][89][90] portal hypertension, 91 vascular malformations, 92 and transplant rejection. 82 The final common event leading to EndMT is activation of transforming growth Authorization for this adaptation has been obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.…”

Signaling mechanisms of the epithelial-mesenchymal transition

“…First described in the 1980s as a cellular phenomenon in the primitive streak of chick embryos, EMT governs many developmental processes such as gastrulation, neural crest development, somite dissociation, and palate and lip fusion ( 1 , 2 ). A similar process termed the endothelial-mesenchymal transition (EndMT) involves the transformation of vascular endothelial cells to mesenchymal cells, which regulates the formation of the valves and septa of the developing heart ( 3 ). In the adult, these developmental programming mechanisms can be awoken and often result in the development of various diseases.…”

Myocardium and BMP signaling are required for endocardial differentiation

“…In the absence of the endocardial progenitors in cloche mutants, myocardial cells exhibit defects in cone assembly (Holtzman et al, 2007). On the other hand, myocardium-derived bone morphogenetic protein (BMP) signaling is crucial for epithelialmesenchymal transformation (EMT) to form endocardial cushions and valves (Jiao et al, 2003;Rivera-Feliciano and Tabin, 2006;Garside et al, 2013). In addition, myocardial-derived BMP has been recently implicated in endocardial proliferation during the endocardial ballooning phase (Dietrich et al, 2014).…”