Blood flow generates forces that regulate cardiac valve development. Sheer stress, for example, promotes endocardial cushion formation, which proliferates and remodels to form the mature valve leaflet, but how stresses co-ordinate later stages of valve development has been unclear. Now, using cultured chick cushion explants, Jonathan Butcher and colleagues manipulate osmotic pressure to expose the developing valve to compressive or tensile stress. In this system, cushions compact after 24 hours in all conditions; however, tissues under compressive stress compact the least, whereas tensile stress promotes compaction. Compressive conditions increase proliferation and BMP activity of cells in the endocardial cushion, demonstrated by nuclear localisation of pSmad 1 and pSmad5. BMP treatment also decreases compaction, an effect blocked by BMP inhibition. Furthermore, partial atrial ligation experiments show that compressive stress also increases BMP activity, and impairs valve thinning and elongation in vivo. Conversely, tensile stress increases compaction of the endocardial cushion in culture, which can be prevented by treatment with the myosin inhibitor. Compressive stress and BMP treatment inhibit non-muscle myosin II expression, shown through pSER-19 immunostaining. Taken together, these data indicate a mechanical switch between compressive stress that drives BMP-mediated growth and tensile stress that promotes valve remodelling.
