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Patricia F. Maness - One of the best experts on this subject based on the ideXlab platform.
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the neural cell adhesion molecule ncam promotes clustering and activation of epha3 receptors in gabaergic interneurons to induce ras homolog gene family member a rhoa rho associated Protein Kinase rock mediated growth cone collapse
Journal of Biological Chemistry, 2016Co-Authors: Chelsea S. Sullivan, Maike Kümper, Brenda S. Temple, Patricia F. ManessAbstract:Establishment of a proper balance of excitatory and inhibitory connectivity is achieved during development of cortical networks and adjusted through synaptic plasticity. The neural cell adhesion molecule (NCAM) and the receptor tyrosine Kinase EphA3 regulate the perisomatic synapse density of inhibitory GABAergic interneurons in the mouse frontal cortex through ephrin-A5-induced growth cone collapse. In this study, it was demonstrated that binding of NCAM and EphA3 occurred between the NCAM Ig2 domain and EphA3 cysteine-rich domain (CRD). The binding interface was further refined through molecular modeling and mutagenesis and shown to be comprised of complementary charged residues in the NCAM Ig2 domain (Arg-156 and Lys-162) and the EphA3 CRD (Glu-248 and Glu-264). Ephrin-A5 induced co-clustering of surface-bound NCAM and EphA3 in GABAergic cortical interneurons in culture. Receptor clustering was impaired by a charge reversal mutation that disrupted NCAM/EphA3 association, emphasizing the importance of the NCAM/EphA3 binding interface for cluster formation. NCAM enhanced ephrin-A5-induced EphA3 autophosphorylation and activation of RhoA GTPase, indicating a role for NCAM in activating EphA3 signaling through clustering. NCAM-mediated clustering of EphA3 was essential for ephrin-A5-induced growth cone collapse in cortical GABAergic interneurons, and RhoA and a principal effector, Rho-Associated Protein Kinase, mediated the collapse response. This study delineates a mechanism in which NCAM promotes ephrin-A5-dependent clustering of EphA3 through interaction of the NCAM Ig2 domain and the EphA3 CRD, stimulating EphA3 autophosphorylation and RhoA signaling necessary for growth cone repulsion in GABAergic interneurons in vitro, which may extend to remodeling of axonal terminals of interneurons in vivo.
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The Neural Cell Adhesion Molecule (NCAM) Promotes Clustering and Activation of EphA3 Receptors in GABAergic Interneurons to Induce Ras Homolog Gene Family, Member A (RhoA)/Rho-Associated Protein Kinase (ROCK)-mediated Growth Cone Collapse.
The Journal of biological chemistry, 2016Co-Authors: Chelsea S. Sullivan, Maike Kümper, Brenda S. Temple, Patricia F. ManessAbstract:Abstract Establishment of a proper balance of excitatory and inhibitory connectivity is achieved during development of cortical networks and adjusted through synaptic plasticity. Neural cell adhesion molecule NCAM and the receptor tyrosine Kinase EphA3 regulate perisomatic synapse density of inhibitory GABAergic interneurons in the mouse frontal cortex through ephrin-A5-induced growth cone collapse. In this study, it was demonstrated that binding of NCAM and EphA3 occurred between the NCAM immunoglobulin-2 (Ig2) domain and EphA3 cysteine-rich domain (CRD). The binding interface was further refined through molecular modeling and mutagenesis and shown to be comprised of complementary charged residues in the NCAM Ig2 domain (Arg156, Lys162) and the EphA3 CRD (Glu248, Glu264). Ephrin-A5 induced co-clustering of surface-bound NCAM and EphA3 in GABAergic cortical interneurons in culture. Receptor clustering was impaired by a charge reversal mutation that disrupted NCAM/EphA3 association, emphasizing the importance of the NCAM/EphA3 binding interface for cluster formation. NCAM enhanced ephrin-A5-induced EphA3 autophosphorylation and activation of RhoA GTPase, indicating a role for NCAM in activating EphA3 signaling through clustering. NCAM-mediated clustering of EphA3 was essential for ephrin-A5-induced growth cone collapse in cortical GABAergic interneurons, and RhoA and a principal effector Rho-Associated Protein Kinase (ROCK) mediated the collapse response. These studies delineate a mechanism in which NCAM promotes ephrin-A5-dependent clustering of EphA3 through interaction of the NCAM Ig2 domain and the EphA3 CRD, stimulating EphA3 autophosphorylation and RhoA signaling necessary for growth cone repulsion in GABAergic interneurons in vitro, which may extend to remodeling of axonal terminals of interneurons in vivo.
Hidenobu Tanihara - One of the best experts on this subject based on the ideXlab platform.
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Potential Role of Rho-Associated Protein Kinase Inhibitor Y-27632 in Glaucoma Filtration Surgery
2013Co-Authors: Megumi Honjo, Hidenobu Tanihara, Takanori Kameda, Nagahisa Yoshimura, Takahiro Kawaji, Makoto AraieAbstract:PURPOSE. To investigate the role of Y-27632, a specific inhibitor of Rho-Associated Protein Kinase (ROCK) in regulating human Tenon fibroblast (HTF) activities including proliferation, adhesion, contraction, migratory response, and myofibroblast transdifferentiation. Effects of Y-27632 on prevention of postoperative scar formation were also examined in a rabbit model of glaucoma filtration surgery. METHODS. After treatment of HTFs with Y-27632, cell toxicity, proliferation, migration, adhesion, and contraction were studied. The cytoskeleton and �-smooth muscle actin (�-SMA) expression were examined via immunohistochemistry. In vivo studies in Japanese white rabbits consisted of a full-thickness sclerostomy followed in the 7-day postoperative period by topical application of Y-27632. Intraocular pressure, morphologic changes in bleb features, and histology of surgical site
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the effect of rho associated Protein Kinase inhibitor on monkey schlemm s canal endothelial cells
Investigative Ophthalmology & Visual Science, 2012Co-Authors: Takanori Kameda, Toshihiro Inoue, Masaru Inatani, Tomokazu Fujimoto, Megumi Honjo, Nanako Kasaoka, Miyuki Inouemochita, Nagahisa Yoshimura, Hidenobu TaniharaAbstract:Purpose To investigate the effect of a specific inhibitor of Rho-Associated Protein Kinase, Y-27632, on monkey Schlemm's canal endothelial (SCE) cells. Methods SCE cells were isolated from cynomolgus monkey eyes. The effects of Y-27632 on aqueous outflow facility were evaluated using enucleated monkey eyes and a constant-pressure perfusion system. The effect of Y-27632 on the barrier function of the confluent SCE-cell monolayer was evaluated by measuring transendothelial electrical resistance (TEER) and fluorescein permeability. Y-27632-induced changes in the intracellular localization of ZO-1, claudin-5, β-catenin, pan-cadherin, and filamentous actin (F-actin) were examined by immunofluorescence. Gene-expression changes induced by Y-27632 were analyzed with microarray, and the functional categories of changed genes were identified by gene ontology analysis. The concentrations of intracellular calcium ions were estimated using Fluo-4/AM and a fluorescence microscope system. Results Y-27632 significantly increased the outflow facility and the number of associated giant vacuoles, decreased TEER of the SCE-cell monolayer, and increased the transendothelial flux of fluorescein. Y-27632 disrupted ZO-1 and claudin-5 expression in a confluent SCE-cell monolayer. Among 12,544 genes, Y-27632 treatment increased the expression of 57 genes and decreased the expression of 15 genes. Gene ontology analysis revealed that changed genes were related to various cellular functions, including regulation of calcium ion transport into the cytosol. Y-27632 partially diminished the A23187-induced increase in intracellular calcium ions. Conclusions Y-27632 increased the permeability of the SCE-cell monolayer in association with disruption of the tight junction, F-actin depolymerization, and changes in various cell functions, including calcium transfer.
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Y-27632, a Rho-Associated Protein Kinase inhibitor, attenuates neuronal cell death after transient retinal ischemia
Graefe's Archive for Clinical and Experimental Ophthalmology, 2008Co-Authors: Akira Hirata, Masaru Inatani, Megumi Honjo, Takahiro Kawaji, Yasuya Inomata, Naoko Yonemura, Hidenobu TaniharaAbstract:Purpose Transient retinal ischemia induces the death of retinal neuronal cells. Postischemic damage is associated with the infiltration of leukocytes into the neural tissue through vascular endothelia. The current study aimed to investigate whether this damage was attenuated by the inhibition of Rho/ROCK (Rho Kinases) signaling, recently shown to play a critical role in the transendothelial migration of leukocytes. Methods Y-27632, a selective inhibitor of ROCK, was injected intravitreally into rat eyes with transient retinal ischemia. Cell loss of the ganglion cell layer (GCL) and thinning of the inner plexiform layer (IPL) with and without the administration of Y-27632 were evaluated by histological anaysis, TUNEL assay and retrograde labeling of retinal ganglion cells (RGCs). To examine the attenuation of leukocyte infiltration in postischemic retinas with the administration of Y-27632, silver nitrate staining and immunohistochemistry using an anti-LCA antibody were performed. Results Cell loss of the GCL and thinning of the IPL were significantly attenuated when 100 nmol Y-27632 was administered within three hours of the induction of ischemia. TUNEL assay and retrograde labeling of RGCs showed a decreased number of apoptotic cells and an increased number of RGCs in Y-27632-injected retinas. Moreover, silver nitrate staining and immunohistochemical analysis using an anti-LCA antibody showed that Y-27632 injection dramatically inhibited leukocyte infiltration and endothelial disarrangement. Conclusions Our data suggest that inhibition of Rho/ROCK signaling offers neuroprotective therapy against postischemic neural damage, by regulating leukocyte infiltration in the neural tissue.
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Potential role of Rho-Associated Protein Kinase inhibitor Y-27632 in glaucoma filtration surgery.
Investigative ophthalmology & visual science, 2007Co-Authors: Megumi Honjo, Hidenobu Tanihara, Takanori Kameda, Nagahisa Yoshimura, Takahiro Kawaji, Makoto AraieAbstract:PURPOSE. To investigate the role of Y-27632, a specific inhibitor of Rho-Associated Protein Kinase (ROCK) in regulating human Tenon fibroblast (HTF) activities including proliferation, adhesion, contraction, migratory response, and myofibroblast transdifferentiation. Effects of Y-27632 on prevention of postoperative scar formation were also examined in a rabbit model of glaucoma filtration surgery. METHODS. After treatment of HTFs with Y-27632, cell toxicity, proliferation, migration, adhesion, and contraction were studied. The cytoskeleton and -smooth muscle actin (-SMA) expression were examined via immunohistochemistry. In vivo studies in Japanese white rabbits consisted of a full-thickness sclerostomy followed in the 7-day postoperative period by topical application of Y-27632. Intraocular pressure, morphologic changes in bleb features, and histology of surgical sites were evaluated. RESULTS. Y-27632 had no direct toxicity or significant effects on cell proliferation of HTF. The cell adhesion assay showed that Y-27632 promoted adhesiveness to both fibronectin and collagen type I. Use of Y-27632 significantly inhibited collagen gel contraction and -SMA expression in HTFs. Y-27632 also increased HTF motility. In vivo, Y-27632 inhibited wound healing and fibroproliferation after filtration surgery and significantly improved surgical outcome compared with the vehicle. Histologic examination revealed that blebs in the Y-27632treated group differed from those in the vehicle-treated group in that they lacked significant collagen deposition in the sclerostomy area. CONCLUSIONS. Y-27632 had profound effects on activities of HTFs and was effective in preventing fibroproliferation and scar formation in a rabbit model of glaucoma surgery. A ROCK inhibitor may be an effective anti-scarring agent after glaucoma filtering surgery. (Invest Ophthalmol Vis Sci. 2007;48: 5549‐5557) DOI:10.1167/iovs.07-0878 T he main cause of failure of glaucoma filtration surgery is postoperative scarring in the filtering bleb. Perioperative administration of antimetabolites such as 5-fluorouracil and mitomycin C (MMC) is effective in limiting the scarring process. However, use of these antiproliferative agents is accom
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Y-27632, a Rho-Associated Protein Kinase inhibitor, attenuates neuronal cell death after transient retinal ischemia.
Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie, 2007Co-Authors: Akira Hirata, Masaru Inatani, Megumi Honjo, Takahiro Kawaji, Yasuya Inomata, Naoko Yonemura, Hidenobu TaniharaAbstract:Transient retinal ischemia induces the death of retinal neuronal cells. Postischemic damage is associated with the infiltration of leukocytes into the neural tissue through vascular endothelia. The current study aimed to investigate whether this damage was attenuated by the inhibition of Rho/ROCK (Rho Kinases) signaling, recently shown to play a critical role in the transendothelial migration of leukocytes. Y-27632, a selective inhibitor of ROCK, was injected intravitreally into rat eyes with transient retinal ischemia. Cell loss of the ganglion cell layer (GCL) and thinning of the inner plexiform layer (IPL) with and without the administration of Y-27632 were evaluated by histological anaysis, TUNEL assay and retrograde labeling of retinal ganglion cells (RGCs). To examine the attenuation of leukocyte infiltration in postischemic retinas with the administration of Y-27632, silver nitrate staining and immunohistochemistry using an anti-LCA antibody were performed. Cell loss of the GCL and thinning of the IPL were significantly attenuated when 100 nmol Y-27632 was administered within three hours of the induction of ischemia. TUNEL assay and retrograde labeling of RGCs showed a decreased number of apoptotic cells and an increased number of RGCs in Y-27632-injected retinas. Moreover, silver nitrate staining and immunohistochemical analysis using an anti-LCA antibody showed that Y-27632 injection dramatically inhibited leukocyte infiltration and endothelial disarrangement. Our data suggest that inhibition of Rho/ROCK signaling offers neuroprotective therapy against postischemic neural damage, by regulating leukocyte infiltration in the neural tissue.
Midori Maekawa - One of the best experts on this subject based on the ideXlab platform.
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molecular dissection of the rho associated Protein Kinase p160rock regulated neurite remodeling in neuroblastoma n1e 115 cells
Journal of Cell Biology, 1998Co-Authors: Masaya Hirose, Midori Maekawa, Masayoshi Uehata, Toshimasa Ishizaki, Naoki Watanabe, Onno Kranenburg, Wouter H Moolenaar, Fumio Matsumura, Haruhiko Bito, Shuh NarumiyaAbstract:A critical role for the small GTPase Rho and one of its targets, p160ROCK (a Rho-Associated coiled coil-forming Protein Kinase), in neurite remodeling was examined in neuroblastoma N1E-115 cells. Using wild-type and a dominant-negative form of p160ROCK and a p160ROCK-specific inhibitor, Y-27632, we show here that p160ROCK activation is necessary and sufficient for the agonist-induced neurite retraction and cell rounding. The neurite retraction was accompanied by elevated phosphorylation of myosin light chain and the disassembly of the intermediate filaments and microtubules. Y-27632 blocked both neurite retraction and the elevation of myosin light chain phosphorylation in a similar concentration-dependent manner. On the other hand, suppression of p160ROCK activity by expression of a dominant-negative form of p160ROCK induced neurites in the presence of serum by inducing the reassembly of the intermediate filaments and microtubules. The neurite outgrowth by the p160ROCK inhibition was blocked by coexpression of dominant-negative forms of Cdc42 and Rac, indicating that p160ROCK constitutively and negatively regulates neurite formation at least in part by inhibiting activation of Cdc42 and Rac. The assembly of microtubules and intermediate filaments to form extended processes by inhibitors of the Rho–ROCK pathway was also observed in Swiss 3T3 cells. These results indicate that Rho/ROCK-dependent tonic inhibition of cell process extension is exerted via activation of the actomysin-based contractility, in conjunction with a suppression of assembly of intermediate filaments and microtubules in many cell types including, but not exclusive to, neuronal cells.
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Calcium sensitization of smooth muscle mediated by a Rho-Associated Protein Kinase in hypertension
Nature, 1997Co-Authors: Masayoshi Uehata, Tamami Morishita, Hiroki Tamakawa, Keiji Yamagami, Jun Inui, Toshimasa Ishizaki, Hiroyuki Satoh, Takashi Ono, Toshio Kawahara, Midori MaekawaAbstract:Abnormal smooth-muscle contractility may be a major cause of disease states such as hypertension, and a smooth-muscle relaxant that modulates this process would be useful therapeutically. Smooth-muscle contraction is regulated by the cytosolic Ca2+ concentration and by the Ca2+ sensitivity of myofilaments: the former activates myosin light-chain Kinase and the latter is achieved partly by inhibition of myosin phosphatase. The small GTPase Rho and its target, Rho-Associated Kinase, participate in this latter mechanism in vitro, but their participation has not been demonstrated in intact muscles. Here we show that a pyridine derivative, Y-27632, selectively inhibits smooth-muscle contraction by inhibiting Ca2+ sensitization. We identified the Y-27632 target as a Rho-Associated Protein Kinase, p160ROCK. Y-27632 consistently suppresses Rho-induced, p160ROCK-mediated formation of stress fibres in cultured cells and dramatically corrects hypertension in several hypertensive rat models. Our findings indicate that p160ROCK-mediated Ca2+ sensitization is involved in the pathophysiology of hypertension and suggest that compounds that inhibit this process might be useful therapeutically.
Chelsea S. Sullivan - One of the best experts on this subject based on the ideXlab platform.
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the neural cell adhesion molecule ncam promotes clustering and activation of epha3 receptors in gabaergic interneurons to induce ras homolog gene family member a rhoa rho associated Protein Kinase rock mediated growth cone collapse
Journal of Biological Chemistry, 2016Co-Authors: Chelsea S. Sullivan, Maike Kümper, Brenda S. Temple, Patricia F. ManessAbstract:Establishment of a proper balance of excitatory and inhibitory connectivity is achieved during development of cortical networks and adjusted through synaptic plasticity. The neural cell adhesion molecule (NCAM) and the receptor tyrosine Kinase EphA3 regulate the perisomatic synapse density of inhibitory GABAergic interneurons in the mouse frontal cortex through ephrin-A5-induced growth cone collapse. In this study, it was demonstrated that binding of NCAM and EphA3 occurred between the NCAM Ig2 domain and EphA3 cysteine-rich domain (CRD). The binding interface was further refined through molecular modeling and mutagenesis and shown to be comprised of complementary charged residues in the NCAM Ig2 domain (Arg-156 and Lys-162) and the EphA3 CRD (Glu-248 and Glu-264). Ephrin-A5 induced co-clustering of surface-bound NCAM and EphA3 in GABAergic cortical interneurons in culture. Receptor clustering was impaired by a charge reversal mutation that disrupted NCAM/EphA3 association, emphasizing the importance of the NCAM/EphA3 binding interface for cluster formation. NCAM enhanced ephrin-A5-induced EphA3 autophosphorylation and activation of RhoA GTPase, indicating a role for NCAM in activating EphA3 signaling through clustering. NCAM-mediated clustering of EphA3 was essential for ephrin-A5-induced growth cone collapse in cortical GABAergic interneurons, and RhoA and a principal effector, Rho-Associated Protein Kinase, mediated the collapse response. This study delineates a mechanism in which NCAM promotes ephrin-A5-dependent clustering of EphA3 through interaction of the NCAM Ig2 domain and the EphA3 CRD, stimulating EphA3 autophosphorylation and RhoA signaling necessary for growth cone repulsion in GABAergic interneurons in vitro, which may extend to remodeling of axonal terminals of interneurons in vivo.
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The Neural Cell Adhesion Molecule (NCAM) Promotes Clustering and Activation of EphA3 Receptors in GABAergic Interneurons to Induce Ras Homolog Gene Family, Member A (RhoA)/Rho-Associated Protein Kinase (ROCK)-mediated Growth Cone Collapse.
The Journal of biological chemistry, 2016Co-Authors: Chelsea S. Sullivan, Maike Kümper, Brenda S. Temple, Patricia F. ManessAbstract:Abstract Establishment of a proper balance of excitatory and inhibitory connectivity is achieved during development of cortical networks and adjusted through synaptic plasticity. Neural cell adhesion molecule NCAM and the receptor tyrosine Kinase EphA3 regulate perisomatic synapse density of inhibitory GABAergic interneurons in the mouse frontal cortex through ephrin-A5-induced growth cone collapse. In this study, it was demonstrated that binding of NCAM and EphA3 occurred between the NCAM immunoglobulin-2 (Ig2) domain and EphA3 cysteine-rich domain (CRD). The binding interface was further refined through molecular modeling and mutagenesis and shown to be comprised of complementary charged residues in the NCAM Ig2 domain (Arg156, Lys162) and the EphA3 CRD (Glu248, Glu264). Ephrin-A5 induced co-clustering of surface-bound NCAM and EphA3 in GABAergic cortical interneurons in culture. Receptor clustering was impaired by a charge reversal mutation that disrupted NCAM/EphA3 association, emphasizing the importance of the NCAM/EphA3 binding interface for cluster formation. NCAM enhanced ephrin-A5-induced EphA3 autophosphorylation and activation of RhoA GTPase, indicating a role for NCAM in activating EphA3 signaling through clustering. NCAM-mediated clustering of EphA3 was essential for ephrin-A5-induced growth cone collapse in cortical GABAergic interneurons, and RhoA and a principal effector Rho-Associated Protein Kinase (ROCK) mediated the collapse response. These studies delineate a mechanism in which NCAM promotes ephrin-A5-dependent clustering of EphA3 through interaction of the NCAM Ig2 domain and the EphA3 CRD, stimulating EphA3 autophosphorylation and RhoA signaling necessary for growth cone repulsion in GABAergic interneurons in vitro, which may extend to remodeling of axonal terminals of interneurons in vivo.
Masayoshi Uehata - One of the best experts on this subject based on the ideXlab platform.
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molecular dissection of the rho associated Protein Kinase p160rock regulated neurite remodeling in neuroblastoma n1e 115 cells
Journal of Cell Biology, 1998Co-Authors: Masaya Hirose, Midori Maekawa, Masayoshi Uehata, Toshimasa Ishizaki, Naoki Watanabe, Onno Kranenburg, Wouter H Moolenaar, Fumio Matsumura, Haruhiko Bito, Shuh NarumiyaAbstract:A critical role for the small GTPase Rho and one of its targets, p160ROCK (a Rho-Associated coiled coil-forming Protein Kinase), in neurite remodeling was examined in neuroblastoma N1E-115 cells. Using wild-type and a dominant-negative form of p160ROCK and a p160ROCK-specific inhibitor, Y-27632, we show here that p160ROCK activation is necessary and sufficient for the agonist-induced neurite retraction and cell rounding. The neurite retraction was accompanied by elevated phosphorylation of myosin light chain and the disassembly of the intermediate filaments and microtubules. Y-27632 blocked both neurite retraction and the elevation of myosin light chain phosphorylation in a similar concentration-dependent manner. On the other hand, suppression of p160ROCK activity by expression of a dominant-negative form of p160ROCK induced neurites in the presence of serum by inducing the reassembly of the intermediate filaments and microtubules. The neurite outgrowth by the p160ROCK inhibition was blocked by coexpression of dominant-negative forms of Cdc42 and Rac, indicating that p160ROCK constitutively and negatively regulates neurite formation at least in part by inhibiting activation of Cdc42 and Rac. The assembly of microtubules and intermediate filaments to form extended processes by inhibitors of the Rho–ROCK pathway was also observed in Swiss 3T3 cells. These results indicate that Rho/ROCK-dependent tonic inhibition of cell process extension is exerted via activation of the actomysin-based contractility, in conjunction with a suppression of assembly of intermediate filaments and microtubules in many cell types including, but not exclusive to, neuronal cells.
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Calcium sensitization of smooth muscle mediated by a Rho-Associated Protein Kinase in hypertension
Nature, 1997Co-Authors: Masayoshi Uehata, Tamami Morishita, Hiroki Tamakawa, Keiji Yamagami, Jun Inui, Toshimasa Ishizaki, Hiroyuki Satoh, Takashi Ono, Toshio Kawahara, Midori MaekawaAbstract:Abnormal smooth-muscle contractility may be a major cause of disease states such as hypertension, and a smooth-muscle relaxant that modulates this process would be useful therapeutically. Smooth-muscle contraction is regulated by the cytosolic Ca2+ concentration and by the Ca2+ sensitivity of myofilaments: the former activates myosin light-chain Kinase and the latter is achieved partly by inhibition of myosin phosphatase. The small GTPase Rho and its target, Rho-Associated Kinase, participate in this latter mechanism in vitro, but their participation has not been demonstrated in intact muscles. Here we show that a pyridine derivative, Y-27632, selectively inhibits smooth-muscle contraction by inhibiting Ca2+ sensitization. We identified the Y-27632 target as a Rho-Associated Protein Kinase, p160ROCK. Y-27632 consistently suppresses Rho-induced, p160ROCK-mediated formation of stress fibres in cultured cells and dramatically corrects hypertension in several hypertensive rat models. Our findings indicate that p160ROCK-mediated Ca2+ sensitization is involved in the pathophysiology of hypertension and suggest that compounds that inhibit this process might be useful therapeutically.