With the term 'mechanotransduction', it is intended the ability of cells to sense and respond to mechanical forces by activating intracellular signal transduction pathways and the relative phenotypic adaptation. While a known role of mechanical stimuli has been acknowledged for developmental biology processes and morphogenesis in various organs, the response of cells to mechanical cues is now also emerging as a major pathophysiology determinant. Cells of the cardiovascular system are typically exposed to a variety of mechanical stimuli ranging from compression to strain and flow (shear) stress. In addition, these cells can also translate subtle changes in biophysical characteristics of the surrounding matrix, such as the stiffness, into intracellular activation cascades with consequent evolution toward pro-inflammatory/pro-fibrotic phenotypes. Since cellular mechanotransduction has a potential readout on long-lasting modifications of the chromatin, exposure of the cells to mechanically altered environments may have similar persisting consequences to those of metabolic dysfunctions or chronic inflammation. In the present review, we highlight the roles of mechanical forces on the control of cardiovascular formation during embryogenesis, and in the development and pathogenesis of the cardiovascular system.In the present contribution, we will focus on the role of mechanical forces in controlling the morphogenesis of the cardiovascular system and on their new emerging role as a pathology determinant. We will also describe how traction forces exerted locally by single cells or forces (e.g., laminar/perturbed shear stress, constant/oscillatory pressure) propagated passively in the tissues are converted into signals regulating intracellular biochemistry and gene expression underlying pathology progression. Definition of Cell Mechanotransduction: Outside-In and Inside-Out Communication in the Complex 3D Environment Similar to classical ligand/receptor interactions, mechanotransduction requires binding of cell surface receptors to their ligands immobilized into the extracellular matrix (ECM), or expressed at the surface of adjacent cells. Differences in the mechanical features of the ECM, or in the geometrical arrangement of receptor binding motifs, can have a direct readout on cell proliferation, differentiation and migratory responses. Mechanical cues are converted into biochemical signals by activation of intracellular cascades transmitted via the cytoskeleton and their components, for example the acto-myosin 'stress' fibers [4], the microtubules [5], the scaffolding proteins [6], and various kinases and phosphatases [7] (Figure 1). Cells 2019, 8, x 2 of 18asymmetric cellular divisions and establishment of initial embryonic polarity. Thereafter, the mechanotransduction process continues in adult life, contributing to tissue growth, homeostasis and, finally, disease programming. In the present contribution, we will focus on the role of mechanical forces in controlling the morphogenesis of the cardiovascular system and on...

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BACKGROUND: Conversion of cardiac stromal cells into myofibroblasts is typically associated with hypoxia conditions, metabolic insults, and/or inflammation, all of which are predisposing factors to cardiac fibrosis and heart failure. We hypothesized that this conversion could be also mediated by response of these cells to mechanical cues through activation of the Hippo transcriptional pathway. The objective of the present study was to assess the role of cellular/nuclear straining forces acting in myofibroblast differentiation of cardiac stromal cells under the control of YAP (yes-associated protein) transcription factor and to validate this finding using a pharmacological agent that interferes with the interactions of the YAP/TAZ (transcriptional coactivator with PDZ-binding motif) complex with their cognate transcription factors TEADs (TEA domain transcription factors), under high-strain and profibrotic stimulation. METHODS: We employed high content imaging, 2-dimensional/3-dimensional culture, atomic force microscopy mapping, and molecular methods to prove the role of cell/nuclear straining in YAP-dependent fibrotic programming in a mouse model of ischemia-dependent cardiac fibrosis and in human-derived primitive cardiac stromal cells. We also tested treatment of cells with Verteporfin, a drug known to prevent the association of the YAP/TAZ complex with their cognate transcription factors TEADs. RESULTS: Our experiments suggested that pharmacologically targeting the YAP-dependent pathway overrides the profibrotic activation of cardiac stromal cells by mechanical cues in vitro, and that this occurs even in the presence of profibrotic signaling mediated by TGF-β1 (transforming growth factor beta-1). In vivo administration of Verteporfin in mice with permanent cardiac ischemia reduced significantly fibrosis and morphometric remodeling but did not improve cardiac performance. CONCLUSIONS: Our study indicates that preventing molecular translation of mechanical cues in cardiac stromal cells reduces the impact of cardiac maladaptive remodeling with a positive effect on fibrosis.