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      Pulsatile Stretch and Shear Stress: Physical Stimuli Determining the Production of Endothelium-Derived Relaxing Factors


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          Mechanical forces generated at the endothelium by fluid shear stress and pulsatile stretch are important in ensuring the continuous release of vasoactive endothelial autacoids. Although the mechanism by which endothelial cells are able to detect and convert these physical stimuli into chemical signals is unclear, this process involves the activation of integrins, G proteins and cascades of protein kinases. The constitutive endothelial nitric oxide synthase (NOS III), classified as a Ca<sup>2+</sup>/calmodulin-dependent isoform, can be activated by shear stress and isometric contraction in the absence of a maintained increase in [Ca<sup>2+</sup>]<sub>i</sub> via a mechanism involving its redistribution within the cytoskeleton/caveolae and the activation of one or more regulatory NOS-associated proteins. Thus it would appear that the intracellular cascades activated by Ca<sup>2+</sup>-elevating receptor-dependent agonists, such as bradykinin, and hemodynamic stimuli are distinct. Rhythmic vessel distension is also able to elicit the synthesis of superoxide anions and the endothelium-derived hyperpolarizing factor which play a role in modulating arterial compliance in certain vascular beds.

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          Most cited references 19

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          Demonstration of mechanical connections between integrins, cytoskeletal filaments, and nucleoplasm that stabilize nuclear structure

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            Tensegrity: the architectural basis of cellular mechanotransduction.

             D. Ingber (1996)
            Physical forces of gravity, hemodynamic stresses, and movement play a critical role in tissue development. Yet, little is known about how cells convert these mechanical signals into a chemical response. This review attempts to place the potential molecular mediators of mechanotransduction (e.g. stretch-sensitive ion channels, signaling molecules, cytoskeleton, integrins) within the context of the structural complexity of living cells. The model presented relies on recent experimental findings, which suggests that cells use tensegrity architecture for their organization. Tensegrity predicts that cells are hard-wired to respond immediately to mechanical stresses transmitted over cell surface receptors that physically couple the cytoskeleton to extracellular matrix (e.g. integrins) or to other cells (cadherins, selectins, CAMs). Many signal transducing molecules that are activated by cell binding to growth factors and extracellular matrix associate with cytoskeletal scaffolds within focal adhesion complexes. Mechanical signals, therefore, may be integrated with other environmental signals and transduced into a biochemical response through force-dependent changes in scaffold geometry or molecular mechanics. Tensegrity also provides a mechanism to focus mechanical energy on molecular transducers and to orchestrate and tune the cellular response.
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              Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase.

              Nitric oxide is a messenger molecule, mediating the effect of endothelium-derived relaxing factor in blood vessels and the cytotoxic actions of macrophages, and playing a part in neuronal communication in the brain. Cloning of a complementary DNA for brain nitric oxide synthase reveals recognition sites for NADPH, FAD, flavin mononucleotide and calmodulin as well as phosphorylation sites, indicating that the synthase is regulated by many different factors. The only known mammalian enzyme with close homology is cytochrome P-450 reductase.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                April 1998
                16 April 1998
                : 35
                : 2
                : 73-84
                Institut für Kardiovaskuläre Physiologie, Klinikum der Johann-Wolfgang-Goethe- Universität, Frankfurt am Main, Deutschland
                25568 J Vasc Res 1998;35:73–84
                © 1998 S. Karger AG, Basel

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                Page count
                Figures: 3, Tables: 1, References: 132, Pages: 12


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