Chopra A, Tabdanov E, Patel H, Janmey PA, Kresh JY. Cardiac myocyte remodeling mediated by N-cadherin-dependent mechanosensing. Am J Physiol Heart Circ Physiol 300: H1252-H1266, 2011. First published January 21, 2011 doi:10.1152 doi:10. /ajpheart.00515.2010 adhesions are crucial in maintaining the structural and functional integrity of cardiac cells. Little is known about the mechanosensitivity and mechanotransduction of cell-to-cell interactions. Most studies of cardiac mechanotransduction and myofibrillogenesis have focused on cell-extracellular matrix (ECM)-specific interactions. This study assesses the direct role of intercellular adhesion, specifically that of N-cadherin-mediated mechanotransduction, on the morphology and internal organization of neonatal ventricular cardiac myocytes. The results show that cadherin-mediated cell attachments are capable of eliciting a cytoskeletal network response similar to that of integrinmediated force response and transmission, affecting myofibrillar organization, myocyte shape, and cortical stiffness. Traction forces mediated by N-cadherin were shown to be comparable to those sustained by ECM. The directional changes in predicted traction forces as a function of imposed loads (gel stiffness) provide the added evidence that N-cadherin is a mechanoresponsive adhesion receptor. Strikingly, the mechanical sensitivity response (gain) in terms of the measured cell-spread area as a function of imposed load (adhesive substrate rigidity) was consistently higher for N-cadherin-coated surfaces compared with ECM protein-coated surfaces. In addition, the cytoskeletal architecture of myocytes on an N-cadherin adhesive microenvironment was characteristically different from that on an ECM environment, suggesting that the two mechanotransductive cell adhesion systems may play both independent and complementary roles in myocyte cytoskeletal spatial organization. These results indicate that cell-to-cell-mediated force perception and transmission are involved in the organization and development of cardiac structure and function.cell-to-cell interaction; myofibrillogenesis; extracellular matrix; cell biomechanics NUMEROUS STUDIES IN CELL MECHANOBIOLOGY have shown that the stiffness of the material on which or within which cells grow has sizeable, specific effects on cell morphology, cytoskeletal structure, motility, differentiation, and proliferation (16,39,43,50,62). Mechanical cues, which can act together with or in opposition to chemical stimuli, are potentially associated with pathological conditions that occur in cancer, fibrotic disease, abnormal wound healing, and cardiac remodeling. The mechanical microenvironment of the cell in vivo is defined by its attachment to the extracellular matrix (ECM) and to other cells via forces generated and transmitted across cell-to-cell junctions constituting a network assembly of cells. Nearly all studies of cell mechanobiology in vitro have focused on the attachment of subconfluent cells to ECM ligands such as fibronectin, collagen, and laminin. ...
Changes in tissue and organ stiffness occur during development and are frequently symptoms of disease. Many cell types respond to the stiffness of substrates and neighboring cells in vitro and most cell types increase adherent area on stiffer substrates that are coated with ligands for integrins or cadherins. In vivo cells engage their extracellular matrix (ECM) by multiple mechanosensitive adhesion complexes and other surface receptors that potentially modify the mechanical signals transduced at the cell/ECM interface. Here we show that hyaluronic acid (also called hyaluronan or HA), a soft polymeric glycosaminoglycan matrix component prominent in embryonic tissue and upregulated during multiple pathologic states, augments or overrides mechanical signaling by some classes of integrins to produce a cellular phenotype otherwise observed only on very rigid substrates. The spread morphology of cells on soft HA-fibronectin coated substrates, characterized by formation of large actin bundles resembling stress fibers and large focal adhesions resembles that of cells on rigid substrates, but is activated by different signals and does not require or cause activation of the transcriptional regulator YAP. The fact that HA production is tightly regulated during development and injury and frequently upregulated in cancers characterized by uncontrolled growth and cell movement suggests that the interaction of signaling between HA receptors and specific integrins might be an important element in mechanical control of development and homeostasis.
In addition to soluble signaling molecules, direct cell-to-cell contact is obligatory in relaying the external cues of the microenvironment controlling the differentiation of adult stem cells to cardiomyocytes. These data indicate that human mesenchymal stem cells are plastic and can be reprogrammed into a cardiomyogenic lineage that may be used in cell-based therapy for treating heart failure.
In this study, we evaluated whether point correlation dimension (PD2), a measure of heart rate variability, can predict hypotension accompanying spinal anesthesia for cesarean delivery. After the administration of spinal anesthesia with bupivacaine, hypotension was defined as systolic blood pressure =75% of baseline within 20 min of intrathecal injection. Using the median prespinal PD2 (3.90) to form 2 groups, LO and HI, all 11 hypotensive patients were in the LO group, and all 11 patients without hypotension were in the HI group. Baseline heart rate in the LO group was 95 bpm (10.2 sd), versus 81 bpm (9.6 sd) in the HI group. PD2 shows promise as a predictor of hypotension in pregnant women receiving spinal anesthesia.
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