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We investigated the anatomical localization, biomechanical properties, and molecular phenotype of myocardial collagen tissue in 40 patients with severe aortic stenosis with preserved ejection fraction and symptoms of heart failure.Two transmural biopsies were taken from the left ventricular free wall. Mysial and nonmysial regions of the collagen network were analyzed. Myocardial collagen volume fraction (CVF) was measured by picrosirius red staining. Young's elastic modulus (YEM) was measured by atomic force microscopy in decellularized slices to assess stiffness. Collagen types I and III were measured as CCompared with controls, patients exhibited increased mysial and nonmysial CVF and nonmysial:mysial CVF ratio (P.05). In patients, nonmysial CVF (r = 0.330; P = .046) and the nonmysial:mysial CVF ratio (r = 0.419; P = .012) were directly correlated with the ratio of maximal early transmitral flow velocity in diastole to early mitral annulus velocity in diastole. Both the CThese findings suggest that, in patients with severe aortic stenosis with preserved ejection fraction and symptoms of heart failure, diastolic dysfunction is associated with increased nonmysial deposition of collagen, predominantly type I, resulting in increased extracellular matrix stiffness. Therefore, the characteristics of collagen tissue may contribute to diastolic dysfunction in these patients.

Resumen Introduccion y objetivos Se ha estudiado la localizacion anatomica, las propiedades biomecanicas y el fenotipo molecular del colageno miocardico tisular en 40 pacientes con estenosis aortica grave, fraccion de eyeccion conservada y sintomas de insuficiencia cardiaca. Metodos Se obtuvieron 2 biopsias transmurales de la pared libre del ventriculo izquierdo. La fraccion del volumen de colageno (FVC) se cuantifico mediante rojo picrosirio y la rigidez, mediante el modulo elastico de Young (YEM) evaluado con microscopia de fuerza atomica en regiones misiales y no misiales. Las FVC de tipos I y III se cuantificaron mediante microscopia confocal en areas con determinacion del YEM. Resultados Comparados con sujetos de control, la FVC misial y no misial y el cociente FVC no misial:misial (p I :FVC III y el YEM aumentaban (p ≤ 0,001) en regiones no misiales respecto de las misiales, con correlacion entre ellos (r = 0,895; p Conclusiones En la estenosis aortica grave con fraccion de eyeccion conservada y sintomas de insuficiencia cardiaca, la disfuncion diastolica se asocia con un deposito no misial de colageno aumentado, predominantemente de tipo I y con mayor rigidez. Las caracteristicas del colageno tisular pueden contribuir a la disfuncion diastolica en estos pacientes.

YAP is a mechanosensitive transcriptional activator with a critical role in cancer, regeneration, and organ size control. Here, we show that force applied to the nucleus directly drives YAP nuclear translocation by decreasing the mechanical restriction of nuclear pores to molecular transport. Exposure to a stiff environment leads cells to establish a mechanical connection between the nucleus and the cytoskeleton, allowing forces exerted through focal adhesions to reach the nucleus. Force transmission then leads to nuclear flattening, which stretches nuclear pores, reduces their mechanical resistance to molecular transport, and increases YAP nuclear import. The restriction to transport is further regulated by the mechanical stability of the transported protein, which determines both active nuclear transport of YAP and passive transport of small proteins. Our results unveil a mechanosensing mechanism mediated directly by nuclear pores, demonstrated for YAP but with potential general applicability in transcriptional regulation.

Cell response to force regulates essential processes in health and disease. However, the fundamental mechanical variables that cells sense and respond to remain unclear. Here we show that the rate of force application (loading rate) drives mechanosensing, as predicted by a molecular clutch model. By applying dynamic force regimes to cells through substrate stretching, optical tweezers, and atomic force microscopy, we find that increasing loading rates trigger talin-dependent mechanosensing, leading to adhesion growth and reinforcement, and YAP nuclear localization. However, above a given threshold the actin cytoskeleton softens, decreasing loading rates and preventing reinforcement. By stretching rat lungs in vivo, we show that a similar phenomenon may occur. Our results show that cell sensing of external forces and of passive mechanical parameters (like tissue stiffness) can be understood through the same mechanisms, driven by the properties under force of the mechanosensing molecules involved., Cells sense mechanical forces from their environment, but the precise mechanical variable sensed by cells is unclear. Here, the authors show that cells can sense the rate of force application, known as the loading rate, with effects on YAP nuclear localization and cytoskeletal stiffness remodelling.