Shear Stress Activates Cytosolic Phospholipase A2(cPLA2) and MAP Kinase in Human Endothelial Cells

Pearce, Michael J.; McIntyre, Thomas M.; Prescott, Stephen M.; Zimmerman, Guy A.; Whatley, Ralph E.

doi:10.1006/bbrc.1996.0089

Cited by 111 publications

(58 citation statements)

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“…In the present study, inhibition of basal and agonist-induced p42 m~pk activation by PD98059 was accompanied by a parallel inhibition of PGI2 release in both 'resting' and stimulated HUVEC. Our ability to detect both p42 m~pk activation and PGI2 release in the absence of agonist is not unexpected; replacement of medium above endothelial cell monolayers subjects the cells to shear stress which is known to promote PGI2 release [23] and to enhance phosphorylation and activation of p42 m~pk [19,20]. Taken together these results demonstrate a central role for p42 m~pk in the control of PGI2 synthesis/release in HUVEC.…”

Section: Discussionsupporting

confidence: 53%

“…Growing evidence from a number of cell types, including terminally differentiated cells, additionally implicates p42 m~pk in the control of acute responses to receptor stimulation such as exocytosis and arachidonic acid release [14,15]. In endothelial cells p42 mapk can be activated by growth factors [16], GPCA [17,18], shear stress [19,20] or inflammatory cytokines (this study) but the functional relevance of stimulus-induced changes in p42 mapk remains to be determined. In the present study we used a novel inhibitor of MEK to explore the potential involvement of p42 mapk in thrombin-driven PGI2 synthesis and in cytokineinduced expression of E-selectin.…”

Section: Discussionmentioning

confidence: 84%

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Inhibition of MAP kinase kinase (MEK) blocks endothelial PGI₂ release but has no effect on von Willebrand factor secretion or E‐selectin expression

et al. 1996

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We have examined the potential role of MAP kinase in the regulation of endothelial cell PGI2 synthesis, vWF secretion and E-selectin expression using the specific MEK inhibitor PD98059. PD98059 dose-dependently attenuated the tyrosine phosphorylation and activation of !}42 mapk in response to thrombin or inflammatory cytokines. Inhibition of thrombinmapk induced p42 activation was paralleled by an inhibitory effect of PD98059 on thrombin-driven PGI2 generation but not on vWF secretion or IL-lo0TNF~-induced E-selectin expression. These results provide evidence for a key role for !142 mapk in the acute regulation of PGI2 synthesis in human endothelial cells and suggest that activation of the MAP kinase cascade is not obligatory for cytokine-stimulated E-selectin expression.

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Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 84%

Inhibition of MAP kinase kinase (MEK) blocks endothelial PGI₂ release but has no effect on von Willebrand factor secretion or E‐selectin expression

et al. 1996

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“…The response to SLIGRL was the same in either case. Blockade of PAR1 cleavage also inhibited thrombin-induced phosphorylation of the mitogenactivated protein kinase, ERK2 (data not shown), which lies downstream of a number of different effector pathways in HU-VEC (35)(36)(37).…”

Section: Resultsmentioning

confidence: 92%

Thrombin Responses in Human Endothelial Cells

O’Brien¹,

Prévost²,

Molino³

et al. 2000

Journal of Biological Chemistry

283

105

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The recent identification of two new thrombin receptors, PAR3 and PAR4, led us to re-examine the basis for endothelial cell responses to thrombin. Human umbilical vein endothelial cells (HUVEC) are known to express PAR1 and the trypsin/tryptase receptor, PAR2. Northern blots detected both of those receptors and, to a lesser extent, PAR3, but PAR4 message was undetectable and there was no response to PAR4 agonist peptides. To determine whether PAR3 or any other receptor contributes to thrombin signaling in HUVEC, PAR1 cleavage was blocked with two selective antibodies and PAR1 activation was inhibited with the antagonist, BMS200261. The antibodies completely inhibited HU-VEC responses to thrombin, but BMS200261 was only partly effective, even though separate studies established that the antagonist completely inhibits PAR1 signaling at the concentrations used. Since peptides mimicking the PAR1 tethered ligand domain can also activate PAR2, we asked whether the remaining thrombin response in the presence of the antagonist could be due in part to the intermolecular transactivation of PAR2 by cleaved PAR1. Evidence that transactivation can occur was obtained in COS-7 cells co-expressing PAR2 and a variant of PAR1 that can be cleaved, but not signal. There was a substantial response to thrombin only in cells expressing both receptors. Conversely, in HUVEC, complete blockade of the thrombin response by the PAR1 antagonist occurred only when signaling through PAR2 was also blocked. From these observations we conclude that 1) PAR1 is the predominant thrombin receptor expressed in HUVEC and cleavage of PAR1 is required for endothelial cell responses to thrombin; 2) although PAR3 may be expressed, there is still no evidence that it mediates thrombin responses; 3) PAR4 is not expressed on HUVEC; and 4) transactivation of PAR2 by cleaved PAR1 can contribute to endothelial cell responses to thrombin, particularly when signaling through PAR1 is blocked. Such transactivation may limit the effectiveness of PAR1 antagonists, which compete with the tethered ligand domain rather than preventing PAR1 cleavage.

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“…Shear stress has been shown to increase both MAPK and Akt phosphorylation in cultured endothelial cells (7,20), but, interestingly, preconditioning of cells with shear stress for 6 h increases caveolin expression and concomitantly eliminates flow-induced ERK1/2 phosphorylation (21). The endothelial cells in the carotid arteries used in this study are preconditioned to shear stress since they have been exposed to blood flow in vivo.…”

Section: Discussionmentioning

confidence: 99%

Differential dependence of stretch and shear stress signaling on caveolin-1 in the vascular wall

Albinsson¹,

Nordström²,

Swärd³

et al. 2008

American Journal of Physiology-Cell Physiology

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The role of caveolae in stretch- versus flow-induced vascular responses was investigated using caveolin 1-deficient [knockout (KO)] mice. Portal veins were stretched longitudinally for 5 min (acute) or 72 h (organ culture). Basal ERK1/2 and Akt phosphorylation were increased in organ-cultured KO veins, as were protein synthesis and vessel wall cross sections. Stretch stimulated acute phosphorylation of ERK1/2 and long-term phosphorylation of focal adhesion kinase (FAK) and cofilin but did not affect Akt phosphorylation. Protein synthesis, and particularly synthesis of smooth muscle differentiation markers, was increased by stretch. These effects did not differ in portal veins from KO and control mice, which also showed the same contractile response to membrane depolarization and inhibition by the Rho kinase inhibitor Y-27632. KO carotid arteries had increased wall cross sections and responded to pressurization (120 mmHg) for 1 h with increased ERK1/2 but not Akt phosphorylation, similar to control arteries. Shear stress by flow for 15 min, on the other hand, increased phosphorylation of Akt in carotids from control but not KO mice. In conclusion, caveolin 1 contributes to low basal ERK1/2 and Akt activity and is required for Akt-dependent signals in response to shear stress (flow) but is not essential for trophic effects of stretch (pressure) in the vascular wall.

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Shear Stress Activates Cytosolic Phospholipase A2(cPLA2) and MAP Kinase in Human Endothelial Cells

Cited by 111 publications

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Inhibition of MAP kinase kinase (MEK) blocks endothelial PGI₂ release but has no effect on von Willebrand factor secretion or E‐selectin expression

Inhibition of MAP kinase kinase (MEK) blocks endothelial PGI₂ release but has no effect on von Willebrand factor secretion or E‐selectin expression

Thrombin Responses in Human Endothelial Cells

Differential dependence of stretch and shear stress signaling on caveolin-1 in the vascular wall

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Shear Stress Activates Cytosolic Phospholipase A2(cPLA2) and MAP Kinase in Human Endothelial Cells

Cited by 111 publications

References 0 publications

Inhibition of MAP kinase kinase (MEK) blocks endothelial PGI2 release but has no effect on von Willebrand factor secretion or E‐selectin expression

Inhibition of MAP kinase kinase (MEK) blocks endothelial PGI2 release but has no effect on von Willebrand factor secretion or E‐selectin expression

Thrombin Responses in Human Endothelial Cells

Differential dependence of stretch and shear stress signaling on caveolin-1 in the vascular wall

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Inhibition of MAP kinase kinase (MEK) blocks endothelial PGI₂ release but has no effect on von Willebrand factor secretion or E‐selectin expression

Inhibition of MAP kinase kinase (MEK) blocks endothelial PGI₂ release but has no effect on von Willebrand factor secretion or E‐selectin expression