RhoA inactivation enhances endothelial barrier function

Carbajal, José M.; Schaeffer, Richard C.

doi:10.1152/ajpcell.1999.277.5.c955

Cited by 109 publications

(93 citation statements)

References 25 publications

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“…Such approaches have been previously used to demonstrate diabetes-related increase in permeability of coronary microvasclature to albumin (21)(22)(23) The precise mechanisms responsible for these observations are not clear. One potential explanation is that statins alter rho-GTPase activity (11,24 -28), and rho signaling pathways have been shown to have a critical role in endothelial barrier function (9,10). However, this biochemical pathway is dependent on the inhibition of HMGCoA reductase activity (11).…”

Section: Discussionmentioning

confidence: 99%

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Statins Ameliorate Endothelial Barrier Permeability Changes in the Cerebral Tissue of Streptozotocin-Induced Diabetic Rats

et al. 2005

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Statins may have favorable effects on endothelial barrier function. The effect of rosuvastatin and simvastatin therapy (10 mg/kg) for 5 weeks on blood-brain barrier (BBB), blood-retinal barrier (BRB), and cardiac muscle permeability of streptozotocin-induced diabetic rats was studied. The size-selective permeability of different vascular beds to a group of fluorescein isothiocyanate dextrans of varying molecular weights was measured. The volume of distribution of 250-, 70-, and 40-kDa dextrans in the cerebral tissue of diabetic rats were significantly increased. The volume of distribution of these dextrans in cerebral tissue was normalized by both statins. Diabetes did not significantly alter the BRB, but both statins decreased the volume of distribution of 70-and 40-kDa dextrans in the retina. The volume of distribution of 40 kDa in cardiac muscle was increased in diabetes, and this change was prevented with statin treatment. Treatment with rosuvastatin and mevalonate (150 mg/kg in drinking water for 5 weeks) did not alter the volume of distribution measurements. We concluded that 1) diabetes in rats is associated with significant changes in the BBB permeability; 2) statin treatment improves the endothelial barrier function in cerebral tissue, retina, and cardiac muscle; and 3) this statin effect could not be attributed to HMGCoA reductase inhibition. Diabetes 54: [2977][2978][2979][2980][2981][2982] 2005 O ne of the sentinel features of atherosclerosis is endothelial cell dysfunction that manifests itself in a variety of ways including poor nitric oxide production, poor vasodilatory response, and increased adhesiveness to leukocytes (1). Another potential endothelial dysfunction commonly observed in diabetes is altered permeability to macromolecules.Diabetes in humans and in animal models has been found to cause significant alterations in endothelial permeability in various vascular beds (2-5). Potential mechanisms underlying the diabetes-related changes in the blood-brain barrier (BBB) include altered expression of key structural and enzymatic proteins, alterations in the lipid composition and fluidity of the membranes, alterations in the neurotransmitter activity, and increased oxidative damage of the endothelial cells (2,6). Another likely contributor to these changes is the activation of protein kinase C that is shown to play an important role in increased permeability of the peripheral and cerebral circulation (7,8). Finally, recent studies have shown that inactivation of the rho-GTPase has a critical role in endothelial barrier function (9,10).Statins are known to have many pleiotropic effects (11). However, the effect of statins on the functional integrity of the microvasculature of diabetic animals has not been well studied. Statins are known to alter endothelial cell function, smooth muscle cell migration and proliferation, and some aspects of vascular inflammation (11). In addition, statins have been shown to improve endothelial barrier permeability in the aorta of Watanabe hyperlipidimic rabbits ...

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Section: Discussionmentioning

confidence: 99%

“…Another likely contributor to these changes is the activation of protein kinase C that is shown to play an important role in increased permeability of the peripheral and cerebral circulation (7,8). Finally, recent studies have shown that inactivation of the rho-GTPase has a critical role in endothelial barrier function (9,10).…”

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confidence: 99%

Statins Ameliorate Endothelial Barrier Permeability Changes in the Cerebral Tissue of Streptozotocin-Induced Diabetic Rats

et al. 2005

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“…ASF formation under stimulated and / or stress conditions and the connection of the tip of ASF to focal adhesion units (FAU) and other cell adhesion factors have been documented (29,30). In the internal surface of the plasma membrane, FAU connect cytoskeleton and ASF.…”

Section: +mentioning

confidence: 99%

Thrombin-Induced Force Development in Vascular Endothelial Cells: Contribution to Alteration of Permeability Mediated by Calcium-Dependent and -Independent Pathways

Nobe¹,

Sone²,

Rutgeerts³

et al. 2005

J Pharmacol Sci

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Abstract. Endothelial cell (EC) barrier dysfunction is associated with many types of vascular diseases. Investigators have hypothesized that altered EC contraction in conjunction with morphological changes may lead to EC dysfunction. However, the nature of EC contraction and its regulatory mechanisms are not fully understood. In this study we measured thrombin-induced force in bovine arterial EC force using EC fibers that were grown in a collagen matrix. Contraction, which occurred in time-and dose-dependent fashion, was elicited by thrombin. The thrombin-enhanced EC layer permeability was correlated with EC fiber contraction. These results suggest that EC contractile response is involved in alteration of EC barrier function. During the initial period of thrombin stimulation, cadherin complexes were disrupted and cell-to-cell connections were reduced. This was dependent on the transient increase in intracellular calcium concentration and myosin phosphorylation. Rho kinase activation led to rearrangement of actin stress fibers (ASF). Paracellular holes were created in the EC layer in parallel to EC morphological change. Our findings suggest that EC layer permeability is regulated by two distinguishable steps. In the initial period, the cell-to-cell connection was reduced in a calcium-dependent fashion. Subsequently, Rho kinase and ASF-mediated force development increased EC layer permeability via morphological change of EC.

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“…Another class of critical regulatory proteins in regulation of endothelial barrier function is the family of Rho GTPases (2,9,14,36,45,47). The family consists of 20 distinct members [Rho (A, B, C); Rac (1, 2, 3); Cdc42; TC10; TCL; Chp (1, 2); RhoG; Rnd (1, 2, 3); RhoBTB (1, 2); RhoD; Rif; and TTF)] (15), of which Cdc42, Rac1, and RhoA are the most characterized (6) and are essential in the relay of signals to the actin cytoskeleton in regulation of activities such as cell adhesion, motility, cell cycle progression, and apoptosis.…”

mentioning

confidence: 99%

PKA inhibits RhoA activation: a protection mechanism against endothelial barrier dysfunction

Qiao

Huang

Lum

2003

American Journal of Physiology-Lung Cellular and Molecular Phys

175

160

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Much evidence indicates that cAMP-dependent protein kinase (PKA) prevents increased endothelial permeability induced by inflammatory mediators. We investigated the hypothesis that PKA inhibits Rho GTPases, which are regulator proteins believed to mediate endothelial barrier dysfunction. Stimulation of human microvascular endothelial cells (HMEC) with thrombin (10 nM) increased activated RhoA (RhoA-GTP) within 1 min, which remained elevated approximately fourfold over control for 15 min. The activation was accompanied by RhoA translocation to the cell membrane. However, thrombin did not activate Cdc42 or Rac1 within similar time points, indicating selectivity of activation responses by Rho GTPases. Pretreatment of HMEC with 10 μM forskolin plus 1 μM IBMX (FI) to elevate intracellular cAMP levels inhibited both thrombin-induced RhoA activation and translocation responses. FI additionally inhibited thrombin-mediated dissociation of RhoA from guanine nucleotide dissociation inhibitor (GDI) and enhanced in vivo incorporation of32P by GDI. HMEC pretreated in parallel with FI showed >50% reduction in time for the thrombin-mediated resistance drop to return to near baseline and inhibition of ∼23% of the extent of resistance drop. Infection of HMEC with replication-deficient adenovirus containing the protein kinase A inhibitor gene (PKA inhibitor) blocked both the FI-mediated protective effects on RhoA activation and resistance changes. In conclusion, the results provide evidence that PKA inhibited RhoA activation in endothelial cells, supporting a signaling mechanism of protection against vascular endothelial barrier dysfunction.

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RhoA inactivation enhances endothelial barrier function

Cited by 109 publications

References 25 publications

Statins Ameliorate Endothelial Barrier Permeability Changes in the Cerebral Tissue of Streptozotocin-Induced Diabetic Rats

Statins Ameliorate Endothelial Barrier Permeability Changes in the Cerebral Tissue of Streptozotocin-Induced Diabetic Rats

Thrombin-Induced Force Development in Vascular Endothelial Cells: Contribution to Alteration of Permeability Mediated by Calcium-Dependent and -Independent Pathways

PKA inhibits RhoA activation: a protection mechanism against endothelial barrier dysfunction

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