Local variation in expression of pro- and antithrombotic factors in vascular endothelium of human autopsy brain

Tohgi, Hideo; Utsugisawa, Kimiaki; Yoshimura, Masahiro; Nagane, Yuriko; Ukitsu, Miyuki

doi:10.1007/s004010051058

Cited by 19 publications

(22 citation statements)

References 36 publications

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“…The coordinated regulation of these critical anti- and procoagulant surface proteins suggests that KLF2 expression can confer a robust anticoagulant endothelial phenotype. Interestingly, the selective lack of expression of TF and PAI-1 in regions of the human carotid artery exposed to atheroprotective blood flow (27) is consistent with a role for KLF2 as a suppressor of these genes in vivo. Furthermore, we found that the IL-1b-mediated increase of a large number of proinflammatory genes was muted by KLF2 ( Figure 2B, cluster III).…”

Section: Figuresupporting

confidence: 56%

Integration of flow-dependent endothelial phenotypes by Kruppel-like factor 2

Parmar¹

2005

Journal of Clinical Investigation

628

646

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In the face of systemic risk factors, certain regions of the arterial vasculature remain relatively resistant to the development of atherosclerotic lesions. The biomechanically distinct environments in these arterial geometries exert a protective influence via certain key functions of the endothelial lining; however, the mechanisms underlying the coordinated regulation of specific mechano-activated transcriptional programs leading to distinct endothelial functional phenotypes have remained elusive. Here, we show that the transcription factor Kruppel-like factor 2 (KLF2) is selectively induced in endothelial cells exposed to a biomechanical stimulus characteristic of atheroprotected regions of the human carotid and that this flow-mediated increase in expression occurs via a MEK5/ERK5/MEF2 signaling pathway. Overexpression and silencing of KLF2 in the context of flow, combined with findings from genome-wide analyses of gene expression, demonstrate that the induction of KLF2 results in the orchestrated regulation of endothelial transcriptional programs controlling inflammation, thrombosis/hemostasis, vascular tone, and blood vessel development. Our data also indicate that KLF2 expression globally modulates IL-1b-mediated endothelial activation. KLF2 therefore serves as a mechano-activated transcription factor important in the integration of multiple endothelial functions associated with regions of the arterial vasculature that are relatively resistant to atherogenesis.

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Section: Figuresupporting

confidence: 56%

Integration of flow-dependent endothelial phenotypes by Kruppel-like factor 2

Parmar¹

2005

Journal of Clinical Investigation

628

646

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“…Consistent with this, TF expression is suppressed by chronic physiological levels of shear stress [30]. However, acute changes in shear stress up-regulate TF both in vivo and in vitro [31], inducing a prothrombotic phenotype exemplified by the characteristics of the endothelium at atheroma-prone sites such as the carotid bifurcation [32]. This is also seen in the present experiments with the upregulation of TF mRNA in untreated cells, which is most probably related to the non-laminar shear stress of changing culture medium at 2 and 4 h. The consequent binding and activation of FVII and FX on the endothelium in these areas would therefore be expected to induce ET-1 synthesis through the PAR2-dependent mechanism described in the present study and hence drive the process of atheroma formation.…”

Section: Discussionsupporting

confidence: 53%

Factor VIIa stimulates endothelin-1 synthesis in TNF-primed endothelial cells by activation of protease-activated receptor 2

et al. 2005

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The mechanisms linking prothrombotic changes to endothelial dysfunction and accelerated atheroma formation have yet to be fully defined. Expression of TF (tissue factor) on the endothelium is potentially an initiating event as binding and activation of FVII (factor VII) can result in thrombosis. Although PAR2 (protease-activated receptor-2) is expressed on vascular endothelium, its precise physiological significance and mechanism of activation have yet to be defined. In the present study, we investigated whether PAR2 can be activated by FVIIa (activated FVII) and induce ET-1 (endothelin-1) synthesis. In bovine aortic endothelial cells pretreated with TNF (tumour necrosis factor-alpha) to increase TF expression, FVIIa stimulated ET-1 synthesis via activation of PAR2. Although FX (factor X) alone was inactive, this response was enhanced by using FVII and FX in combination. Inhibition of the proteolytic activity of FVIIa abolished the response. The PAR2 agonist peptide SLIGKV also enhanced ET-1 release on TNF-pretreated cells. The response to FVIIa was inhibited by a PAR2 antagonist peptide FSLLRY. Inhibition of the p38 MAPK (mitogen-activated protein kinase) reduced PAR2 expression and the ET-1 response. In summary, FVIIa can stimulate ET-1 synthesis in endothelial cells by activating PAR2, demonstrating a potential link between thrombotic processes and endothelial cell dysfunction.

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“…The elevated levels of tPA in patients with extensive WML coincided with low levels of PAI-1 in these patients. PAI-1 and tPA are extensively present in the small blood vessels of the white matter, 22 and both proteins may be involved in mediating neuronal cell damage. 23 Although the exact mechanisms are still unknown, low activity of PAI-1 is associated with tPA-induced tissue damage 24 resulting from NMDA-induced ischemia by tPA after crossing the blood-brain barrier.…”

Section: Discussionmentioning

confidence: 99%

Endothelial Activation in Lacunar Stroke Subtypes

Knottnerus

Govers‐Riemslag

Hamulyák

et al. 2010

Stroke

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Background and Purpose-Lacunar stroke (LS) can be subtyped according to the absence (isolated lacunar infarct [ILA]) or presence of concomitant white matter lesions (WML) and/or asymptomatic lacunar infarcts. Endothelial activation is thought to play a pivotal role in the subtype with WML and/or asymptomatic lacunar infarcts. The aim of this study was to evaluate whether endothelial activation is associated with WML and/or asymptomatic lacunar infarcts in LS patients. Here, we determined levels of circulating blood markers of endothelial function in LS patients. Methods-In 149 patients, all of whom had brain-MRI, levels of tissue plasminogen activator (tPA), plasminogen activator inhibitor type 1 (PAI-1), tPA-PAI-1 complex, von Willebrand factor, tissue factor, thrombomodulin, and coagulation factor VIII were determined. Levels of blood markers were related to subtypes of LS and adjusted for age, gender, and vascular risk factors. Results-In subtypes of LS, tPA activity was increased in patients with WML (0.79 IU/mL vs 0.44 IU/mL for ILA;Pϭ0.02) and PAI-1-antigen levels were lowest in patients with WML (27.5 ng/mL vs 44.0 ng/mL for ILA; Pϭ0.02).The association between WML and PAI-1 remained significant after multivariable analysis (OR, 0.99; 95% CI, 0.98 -1.00 per ng/mL change of PAI-1; Pϭ0.04). Conclusions-We found further evidence for the hypothesis of endothelial activation in the subtype of LS caused by a diffuse small vessel vasculopathy, as we found higher levels of tPA in patients with concomitant extensive WML than in those with ILA. Second, low levels of PAI-1 were associated with WML. We postulate that differences in activity of components of the fibrinolytic system might contribute to WML development. (Stroke. 2010;41:1617-1622.)

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Local variation in expression of pro- and antithrombotic factors in vascular endothelium of human autopsy brain

Cited by 19 publications

References 36 publications

Integration of flow-dependent endothelial phenotypes by Kruppel-like factor 2

Integration of flow-dependent endothelial phenotypes by Kruppel-like factor 2

Factor VIIa stimulates endothelin-1 synthesis in TNF-primed endothelial cells by activation of protease-activated receptor 2

Endothelial Activation in Lacunar Stroke Subtypes

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