Thrombin receptor peptide inhibits thrombin-induced increase in endothelial permeability by receptor desensitization.

Lum, Hazel; Andersen, Thomas T.; Siflinger-Birnboim, Alma; Tiruppathì, Chinnaswamy; Goligorsky, Michael S.; Fenton, John W.; Malik, Asrar B.

doi:10.1083/jcb.120.6.1491

Cited by 72 publications

(40 citation statements)

References 36 publications

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“…6,7 The other striking change in ECs SK was the decreased tyrosine phosphorylation of PECAM-1 ( Figure 3D). Resting ECs have low levels of tyrosine phosphorylation 47,48 but this can be increased by factors such as VEGF, 61 TNF, 62 and thrombin, 63 which are known permeability-inducing agents and decrease cell-cell interactions. Conversely, phosphorylation is inhibited by the antipermeability agent angiopoietin-1 64 and in migrating ECs.…”

Section: Discussionmentioning

confidence: 99%

Sphingosine kinase-1 enhances endothelial cell survival through a PECAM-1–dependent activation of PI-3K/Akt and regulation of Bcl-2 family members

Limaye

Hahn

et al. 2005

Blood

165

129

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Sphingosine-1-phosphate (S1P), the bioactive product of sphingosine kinase (SK) activation, is a survival factor for endothelial cells. The mechanism of SK-mediated survival was investigated in endothelial cells with moderately raised intracellular SK activity. Overexpression of SK mediated survival primarily through the activation of the phosphatidyl inositol 3-kinase (PI-3K)/protein kinase B (Akt/PKB) pathway and an associated up-regulation of the antiapoptotic protein B cell lymphoma gene 2 (Bcl-2) and down-regulation of the proapoptotic protein bisindolylmaleimide (Bcl-2 interacting mediator of cell death; Bim). In addition there was an up-regulation and dephosphorylation of the junctional molecule platelet endothelial cell adhesion molecule-1 (PECAM-1), which was obligatory for activation of the PI-3K/Akt pathway, for SK-induced cell survival, and for the changes in the apoptosis-related proteins. Thus, raised intracellular SK activity induced a molecule involved in cell-cell interactions to augment cell survival through a PI-3K/Akt-dependent pathway. This is distinct from the activation of both PI-3K/Akt and mitogen-activated pro- IntroductionEndothelial cell (EC) survival is regulated by cell-matrix and cell-cell interactions and by growth factors. Cell-matrix attachments are mediated by the integrins, and integrin ligation triggers downstream signaling events that inhibit apoptosis or anoikis. 1,2 Two cell-cell adhesion molecules are critical in the control of endothelial cell survival. The junctional molecule platelet endothelial cell adhesion molecule-1 (PECAM-1; CD31), a 130-kDa member of the immunoglobulin-immunoreceptor tyrosine-based inhibitory motif (Ig-ITIM) family of inhibitory receptors, possesses a functional cytoplasmic ITIM domain, is constitutively and abundantly expressed on normal endothelium 3 regulating leukocyte transmigration 4 and acts as a structural protein in cell-cell attachments. PECAM-1 is also able to suppress programmed cell death 5-9 by virtue of homophilic interactions. VE-cadherin, an endothelial-specific major structural protein involved in adherens junctions, is also involved in mediating the antiapoptotic effects of vascular endothelial cell growth factor 10 (VEGF). VEGF and basic fibroblast growth factor (bFGF) prevent EC apoptosis through activation of the phosphatidyl inositol 3-kinase (PI-3K)/protein kinase B (Akt/PKB) pathway and the Raf/MEK/MAPK (relative activity factor/mitogen-induced extracellular kinase/mitogenactivated protein kinase) pathway, both of which are critical pathways promoting cell survival. [11][12][13][14][15][16] Serum is also a recognized trophic factor for ECs since they undergo apoptosis within 24 hours of serum deprivation. 16 The protective factors in serum have been attributed to lysophosphatidic acid, sphingosine-1-phosphate (S1P), [17][18][19] and high-density lipoproteins. 20 The lipid mediator S1P is formed by the phosphorylation of membrane-associated sphingosine by sphingosine kinase (SK). S1P is stored in high concentrations in th...

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Section: Discussionmentioning

confidence: 99%

Sphingosine kinase-1 enhances endothelial cell survival through a PECAM-1–dependent activation of PI-3K/Akt and regulation of Bcl-2 family members

Limaye

Hahn

et al. 2005

Blood

165

129

View full text Add to dashboard Cite

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“…Acting via the protease activated receptor-1 (PAR-1), thrombin causes within minutes an increase in cultured endothelial monolayer permeability associated with the formation of gaps between adjacent endothelial cells, the activation of contractile mechanisms within the endothelial cells, and changes in cell-cell junction organization (9,10,15,20). However, it is not clear that these responses in cultured endothelial cells to thrombin are representative of the direct action of thrombin on the endothelial barrier in intact organs.…”

mentioning

confidence: 90%

Thrombin increases permeability only in venules exposed to inflammatory conditions

Curry

Zeng

Adamson

2003

American Journal of Physiology-Heart and Circulatory Physiology

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Thrombin is widely used to stimulate a variety of responses in cultured endothelial cell monolayers as a model of acute vascular endothelial reponse to inflammatory mediators. However, preliminary results indicated that rat mesenteric venules did not respond acutely to thrombin. We tested the hypothesis that rat venules would respond to thrombin 24 h after prior injury by microperfusion. Vessel responsiveness was measured as hydraulic conductivity ( Lp). When venules were exposed to rat thrombin (10 U/ml) within 2 h of initial perfusion with vehicle control, there was no increase in Lp of any vessel from a mean baseline of 1.2 ± 0.2 × 10–7 cm·s–1·cmH2O–1. In contrast, when perfused with thrombin at 25–27 h after initial perfusion, every venule responded to thrombin with a transient increase in Lp. The mean peak Lp on day 2 in response to thrombin was 24 ± 4.2 × 10–7 cm·s–1·cmH2O–1. Our results suggest that prior endothelial injury modifies the endothelial cell phenotype and alters the response of endothelial cells to thrombin after 24 h. Phenotypic plasticity of endothelial cells may play a key role in the regulation of permeability of some endothelial cells in culture and in intact venules, where localized leaky sites may form where there had been a previous inflammatory response.

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“…The activation responses of the Rho GTPases in HMEC were investigated by stimulation with thrombin, a mediator known to increase vascular endothelial permeability to albumin (19,30). Activated RhoA, Cdc42, and Rac1 were determined by affinity-binding assay for GST-fusion protein targets of the Rho GTPases.…”

Section: Regulation Of Transendothelial Resistance By Pkamentioning

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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Thrombin receptor peptide inhibits thrombin-induced increase in endothelial permeability by receptor desensitization.

Cited by 72 publications

References 36 publications

Sphingosine kinase-1 enhances endothelial cell survival through a PECAM-1–dependent activation of PI-3K/Akt and regulation of Bcl-2 family members

Sphingosine kinase-1 enhances endothelial cell survival through a PECAM-1–dependent activation of PI-3K/Akt and regulation of Bcl-2 family members

Thrombin increases permeability only in venules exposed to inflammatory conditions

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

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