Getting Physical With the Aortic Valve

Abstract

Mammalian cells and tissues rely on continuous interactions with the structural, physical, and soluble chemical environment to adapt to rapidly changing conditions. This ensures the continuation of proper physiological functions, accurate developmental cues during embryogenesis, containment of chronic pathological changes, and efficient repair of acute injuries. As part of cell regulation, the mechanical status of cells is constantly undergoing adjustment through coordinated responses to changes of intracellular tension imposed by internal and external forces and by encounters with extracellular matrices of varying stiffness.1,2 The role of extracellular proteins in mechanoregulated cell biology has emerged over the last decade in studies of fibrosis—the differentiation of myofibroblasts that express contractile α-smooth muscle actin (α-SMA) organized into stress fibers. Myofibroblast differentiation requires sustained mechanical tension that in turn is dependent on the stiffness of the extracellular matrix as sensed through integrin adhesion sites in the cell membrane.3 A critical soluble protein required for myofibroblast differentiation is transforming growth factor-β (TGF-β)4 that is secreted from myofibroblasts and, in an autocrine loop, can stimulate the cell via TGF-β receptors. However, secreted TGF-β binds to the extracellular matrix via a fibronectin splice variant (TGF-β latent complex), making it unavailable to the cell and preventing differentiation.5 In 2007, Wipff et al6 showed that TGF-β availability depends on the matrix …