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      Microtubule-Dependent Regulation of Vasomotor Tone Requires Rho-Kinase

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          Changes in microtubule polymerization state have been shown to affect many cellular events, including the contractile properties of smooth muscle. We have previously shown that depolymerization of microtubules causes significant vasoconstriction in arterioles. This vasoconstriction does not require the endothelium or an increase in vascular smooth muscle Ca<sup>2+</sup>. Consequently, we hypothesized that a Ca<sup>2+</sup>-sensitizing mechanism may be involved in the constrictor response. The purpose of these experiments was to further elucidate cell signaling pathways responsible for vasoconstriction following microtubule disruption. Rat skeletal muscle arterioles were isolated, cannulated and pressurized without intraluminal flow. All arterioles used for experiments developed spontaneous, myogenic tone (54% of passive diameter). Microtubule depolymerization with colcemid or vinblastine caused arterioles to constrict by an additional 20% from resting basal diameter. In addition, arterioles treated with colcemid showed significantly enhanced responsiveness to norepinephrine and reduced responsiveness to adenosine. To investigate a role for Rho-kinase, vessels were incubated with inhibitors of the Rho-kinase pathway – Y-27632 or C3 exoenzyme. Inhibition of Rho-kinase significantly inhibited the constriction associated with colcemid-induced microtubule depolymerization. Inhibition of Rho-kinase also abolished the increased responsiveness to norepinephrine whereas adenosine responsiveness continued to be reduced. By comparison, inhibition of the tyrosine kinase, Src, with PP2 did not have any effect on the colcemid-induced changes in vascular tone or reactivity. These data indicate that the vasoconstriction and enhanced norepinephrine reactivity associated with microtubule disruption involves a Ca<sup>2+</sup>-sensitization process that is mediated by the Rho-kinase pathway.

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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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            Discovery of a Novel, Potent, and Src Family-selective Tyrosine Kinase Inhibitor

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              Characterization of p190RhoGEF, a RhoA-specific guanine nucleotide exchange factor that interacts with microtubules.

              Rho family GTPases control numerous cellular processes including cytoskeletal reorganization and transcriptional activation. Rho GTPases are activated by guanine nucleotide exchange factors (GEFs) which stimulate the exchange of bound GDP for GTP. We recently isolated a putative GEF, termed p190RhoGEF that binds to RhoA and, when overexpressed in neuronal cells, induces cell rounding and inhibits neurite outgrowth. Here we show that the isolated tandem Dbl homology/pleckstrin homology domain of p190RhoGEF activates RhoA in vitro, but not Rac1 or Cdc42, as determined by GDP release and protein binding assays. In contrast, full-length p190RhoGEF fails to activate RhoA in vitro. When overexpressed in intact cells, however, p190RhoGEF does activate RhoA with subsequent F-actin reorganization and serum response factor-mediated transcription. Immunofluorescence studies show that endogenous p190RhoGEF localizes to distinct RhoA-containing regions at the plasma membrane, to the cytosol and along microtubules. In vitro and in vivo binding experiments show that p190RhoGEF directly interacts with microtubules via its C-terminal region adjacent to the catalytic Dbl homology/pleckstrin homology domain. Our results indicate that p190RhoGEF is a specific activator of RhoA that requires as yet unknown binding partners to unmask its GDP/GTP exchange activity in vivo, and they suggest that p190RhoGEF may provide a link between microtubule dynamics and RhoA signaling.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                April 2002
                10 May 2002
                : 39
                : 2
                : 173-182
                Cardiovascular Research Institute, Department of Medical Physiology, Texas A&M University System Health Science Center, College Station, Tex., USA
                57765 J Vasc Res 2002;39:173–182
                © 2002 S. Karger AG, Basel

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                Page count
                Figures: 8, References: 29, Pages: 10
                Research Paper


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