Valvulogenesis: the moving target

Abstract

Valvulogenesis is an extremely complex process by which a fragile gelatinous matrix is populated and remodelled during embryonic development into thin fibrous leaflets capable of maintaining unidirectional flow over a lifetime. This process occurs during exposure to constantly changing haemodynamic forces, with a success rate of approximately 99%. Defective valvulogenesis results in impaired cardiac function and lifelong complications. This review integrates what is known about the roles of genetics and mechanics in the development of valves and how changes in either result in impaired morphogenesis. It is hoped that appropriate developmental cues and phenotypic endpoints could help engineers and clinicians in their efforts to regenerate living valve alternatives.

Figure 1

General stages of atrioventricular and outflow tract valve development.

Figure 2

Molecular regulation of endocardial to mesenchymal transformation (EMT) as discovered in (a) chick and (b) mouse models. The coordinated interaction of VEGF, TGF-β, BMP, NOTCH, hyaluronan and wnt/β-catenin result in proper mesenchymal invasion into the cardiac jelly. CM, cell membrane; NM, nuclear membrane.

Figure 3

The regulation of post-cushion valve maturation to thin fibrous leaflets also includes EGF receptor signalling in addition to differential signalling of the pathways in figure 2c. CM, cell membrane; NM, nuclear membrane. (+) denotes positive potentiometer of particular pathway.

Figure 4

Periostin is a strong candidate protein involved in the delamination of primitive cushions from the myocardial wall and maintenance of a fibroblastic phenotype. AV cushion mesenchyme cultured in vitro (a) spontaneously differentiates into cartilage as demonstrated by Alcain blue staining in (b), which can be inhibited by a conditioned medium from lower density cultures, suggesting the presence of a secreted inhibitor. Periostin (green) is expressed strongly at (c) the myocardial/mesenchymal boarder in both outflow and (d) atrioventricular valves. (e) Cushion micromass cultures treated with periostin overexpressing virus remain mesenchymal, (f) but the addition of exogenous BMP-2 drastically reduces periostin expression concomitant with osteogenic differentiation.