NOTCH is an intercellular signaling pathway implicated in multiple aspects of organismal development, 9 including the patterning and morphogenesis of the cardiac chambers and valves. Whereas early EMT defects are embryonically lethal, aberrant post-EMT valvulogenic processes result in valve congenital and adult-onset valve disease, making the identification of causative genes an important challenge. 7 The molecular mechanisms of valve development are generally conserved between both sets of valves and involve osteochondrogenic differentiation of mesenchymal precursors. 6 The development of the arterial valves, also called semilunar valves (SLV), is characterized by the contribution of cardiac neural crest (CNC)–derived cells that participate in OFT septation and valve remodeling. 5 Later remodeling by condensation and elongation yields atrioventicular and arterial valves that ensure unidirectional blood flow in the mature heart. 4 Growth and proliferation of this newly formed mesenchyme results in EC fusion and heart septation by E14.5. 3 Valve formation, best characterized in the mouse, begins with an epithelial–mesenchymal transition (EMT), whereby endocardial cells in the mouse E9.5 atrioventricular canal (AVC) and E10.5 outflow tract (OFT) detach from each other to yield mesenchyme cells of the endocardial cushions (EC), which constitute the anlagen for valves and septa. Patients with aortic valve (AV) disease at any age manifest some type of structural malformation frequently in association with aortic coarctation or aneurysm, suggesting a common underlying developmental mechanism affecting the entire aortic root and thoracic aorta. 2 A BAV predisposes to valve calcification and stenosis, and complications in 30% of BAV patients result in more morbidity and mortality than all other CHD combined. However, these estimates do not take into account the bicuspid aortic valve (BAV), which is present in ≈0.5% to 2% of the population. 1 Heart valve malformations, occurring either in isolation or in the context of syndromic disease, account for about one third of all CHDs.
Accordingly, addition of soluble heparin-binding EGF-like growth factor to Jag1-mutant outflow tract explant cultures rescued the hyperproliferative phenotype.Ĭongenital heart defects (CHDs) are the most common structural anomalies, affecting 0.8% of live births worldwide. Hbegf expression in embryonic endocardial cells could be readily activated through a RBPJ-binding site, identifying Hbegf as an endocardial Notch target. Significantly, the negative regulator of mesenchyme proliferation, Hbegf, was markedly reduced in Jag1-mutant valves. Gene profiling revealed upregulated Bmp signaling in Jag1-mutant valves, providing a molecular basis for the hyperproliferative phenotype. Valve dysmorphology was associated with increased mesenchyme proliferation, indicating that Jag1-Notch1 signaling restricts mesenchyme cell proliferation non–cell autonomously. Mice lacking endocardial Jag1, Notch1, or RBPJ displayed enlarged valve cusps, bicuspid aortic valve, and septal defects, indicating that endocardial Jag1 to Notch1 signaling is required for post–epithelial–mesenchymal transition valvulogenesis. Using cardiac-specific conditional targeted mutant mice, we find that endothelial/endocardial deletion of Mib1-Dll4-Notch1 signaling, possibly favored by Manic-Fringe, is specifically required for cardiac epithelial–mesenchymal transition. Customer Service and Ordering Information.Stroke: Vascular and Interventional Neurology.Journal of the American Heart Association (JAHA).Circ: Cardiovascular Quality & Outcomes.Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB).