Heart valve formation during vertebrate embryogenesis is characterized by the initial formation of endocardial cushions in the atrioventricular (AV) canal and outflow tract (OFT), followed by the proliferation of heart valve progenitor cells and the remodeling of primordial valves (3,44,48). At the end of this process, the mature valves consist of elongated leaflets composed primarily of stratified extracellular matrix (ECM) layers and supporting structures. The early stages of endocardial cushion formation and remodeling are similar, but not identical, for the arterial semilunar valves and for the tricuspid and mitral AV valves. In both the AV canal and OFT, endocardial cushions form through an epithelial-to-mesenchymal transition (EMT) in which a subpopulation of endothelial cells transdifferentiates into mesenchyme in response to signals secreted from the myocardium (44). These cushions then go through a highly proliferative phase and fuse to form highly cellular undifferentiated valve primordia that contain the precursors of the individual valves (13, 36). The valve primordia undergo a process of remodeling characterized by reduced proliferation and generation of organized collagen-, elastin-, and proteoglycan-rich ECM strata of the elongated leaflets. Although the mature structures of the semilunar valve cusps are different from the AV valve leaflets and supporting chordae tendineae, the stratification of the valve ECM compartments is similar for both sets of valves relative to the direction of blood flow in the mature heart. However, the semilunar and AV valves differ in the cells that migrate into these structures from extracardiac sources in the embryo, with neural crest cells contributing to the OFT and epicardial-derived cells incorporating into the AV canal.Formation of the semilunar and AV valves is dependent on common signaling pathways, although the specific components of each pathway may be different for the individual valves. Studies in mouse, chicken, and zebrafish embryos as well as human genetic analyses have implicated several sig-390 1548-9213/05 8.00 ©2005 Int. Union Physiol. Sci./Am. Physiol. Soc.
Valve Development and Congenital Heart DiseaseThe heart is the first organ to form in the embryo, and congenital cardiovascular anomalies are responsible for between 16-45% of prenatal deaths (38,54,55). With the increased use of echocardiography in newborns and the advent of fetal ultrasound, the incidence of congenital heart defects (CHD) is now estimated as between 1.2-1.4% of all live births (Table 1) (25). Newborn death due to CHD is second only to infection, and 38% of children diagnosed with a defect will undergo surgical or catheterization-based interventions at least once in their lifetime.Valvular defects account for 20-25% of CHD (25, 37) and include bicuspid aortic valve, pulmonary, or tricuspid atresia and Ebstein's anomaly. Congenital heart valve disease can be caused by genetic or environmental factors, and, with rare exceptions, the specific etiologies of the lesions are unknown. ...