MEK1/2 inhibition attenuates vascular ETA and ETB receptor alterations after cerebral ischaemia

Henriksson, Marie Arsenian; Stenman, Emelie; Vikman, Petter; Edvinsson, Lars

doi:10.1007/s00221-006-0753-7

Cited by 50 publications

(60 citation statements)

References 44 publications

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“…This difference was not seen in other studies (Henriksson et al, 2007a;Stenman et al, 2002Stenman et al, , 2007 and may reflect a relatively small ET A receptor upregulation much less pronounced than in the case of the ET B receptor.…”

Section: Ischemic Strokecontrasting

confidence: 62%

“…occluded MCAs when compared with contralateral MCAs and ipsilateral MCAs from sham-operated rats (Henriksson et al, 2007a). This difference was not seen in other studies (Henriksson et al, 2007a;Stenman et al, 2002Stenman et al, , 2007 and may reflect a relatively small ET A receptor upregulation much less pronounced than in the case of the ET B receptor.…”

Section: Ischemic Strokementioning

confidence: 60%

“…Indeed, ET B receptors were visualized in the smooth muscle cell layer of occluded MCA segments using immunohistochemistry, confocal microscopy, and colocalization of the receptors with the smooth muscle cell marker b-actin (Figure 1) (Henriksson et al, 2007a;Maddahi and Edvinsson, 2008). Interestingly, permanent MCAO did not result in ET B upregulation in the occluded MCA (unpublished data).…”

Section: Ischemic Strokementioning

confidence: 88%

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Vascular plasticity in cerebrovascular disorders

Edvinsson

Povlsen

2011

J Cereb Blood Flow Metab

115

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Cerebral ischemia remains a major cause of morbidity and mortality with little advancement in subacute treatment options. This review aims to cover and discuss novel insight obtained during the last decade into plastic changes in the vasoconstrictor receptor profiles of cerebral arteries and microvessels that takes place after different types of stroke. Receptors like the endothelin type B, angiotensin type 1, and 5-hydroxytryptamine type 1B/1D receptors are upregulated in the smooth muscle layer of cerebral arteries after different types of ischemic stroke as well as after subarachnoid hemorrhage, yielding rather dramatic changes in the contractility of the vessels. Some of the signal transduction processes mediating this receptor upregulation have been elucidated. In particular the extracellular regulated kinase 1/2 pathway, which is activated early in the process, has proven to be a promising therapeutic target for prevention of vasoconstrictor receptor upregulation after stroke. Together, those findings provide new perspectives on the pathophysiology of ischemic stroke and point toward a novel way of reducing vasoconstriction, neuronal cell death, and thus neurologic deficits after stroke.

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Section: Ischemic Strokecontrasting

confidence: 62%

Section: Ischemic Strokementioning

confidence: 60%

Section: Ischemic Strokementioning

confidence: 88%

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Vascular plasticity in cerebrovascular disorders

Edvinsson

Povlsen

2011

J Cereb Blood Flow Metab

115

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“…Transcriptional upregulation of ET A and ET B receptors has been reported in rat cerebral arteries after using some injury models like experimental cerebral ischemia and organ culture [10,19,27,28]. In all cases, the receptor upregulation occurred in the smooth muscle cells.…”

Section: Discussionmentioning

confidence: 99%

“…Increased ERK1/2 phosphorylation has been observed in the ischemic area after both transient and permanent middle cerebral occlusion, as well as after global ischemia [16,17]. Consequently, inhibitors of ERK1/2 and MEK1/2 have been effective in reducing the infarct size in cerebral ischemia [18,19], and in SAH [20]. ERK1/2 is also activated in the cerebral arteries of the ischemic brain, pointing towards a role in vascular alterations [21].…”

Section: Introductionmentioning

confidence: 99%

Secondhand smoke exposure induces Raf/ERK/MAPK-mediated upregulation of cerebrovascular endothelin ETA receptors

Cao

Zhang

et al. 2011

BMC Neurosci

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BackgroundCigarette smoking enhances the risk of stroke. However, the underlying molecular mechanisms are largely unknown. The present study established an in vivo rat secondhand cigarette smoking (SHS) model and examined the hypothesis that SHS upregulates endothelin receptors with increased cerebrovascular contraction via the Raf/extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinases (MAPK) pathway.ResultsRats were exposed to SHS for up to 8 weeks. The cerebral artery vasoconstriction was recorded by a sensitive myograph. The mRNA and protein expressions for endothelin receptors in cerebral arteries were studied by real-time PCR and Western blot. Compared to fresh air exposed rats, cerebral arteries from SHS rats exhibited stronger contractile responses (P < 0.05) mediated by endothelin type A (ETA) receptors. The expressions of mRNA and protein for ETA receptors in the cerebral arteries from SHS rats were higher (P < 0.05) than that in control. SHS did not affect endothelin type B (ETB) receptor-mediated contractions, mRNA or protein levels. The results suggest that SHS upregulates ETA, but not ETB receptors in vivo. After SHS exposure, the mRNA levels of Raf-1 and ERK1/2, the protein expression of phosphorylated (p)-Raf-1 and p-ERK1/2 were increased (P < 0.05). Raf-1 inhibitor, GW5074 suppressed the enhanced ETA receptor-mediated contraction, mRNA and protein levels induced by SHS. In addition, GW5074 inhibited the SHS-caused increased mRNA and phosphorylated protein levels of Raf-1 and ERK1/2, suggesting that SHS induces activation of the Raf/ERK/MAPK pathway.ConclusionsSHS upregulates cerebrovascular ETA receptors via the Raf/ERK/MAPK pathway, which provides novel understanding of mechanisms involved in SHS-associated stroke.

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Dual roles of the MAPK/ERK1/2 cell signaling pathway after stroke

Sawe

Steinberg

Zhao

2008

J of Neuroscience Research

208

175

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Extracellular signal-regulated kinase 1/2 (ERK1/2), one of the best-characterized members of the mitogen-activated protein kinase (MAPK) family, mediates a range of activity from metabolism, motility, and inflammation to cell death and survival. It is phosphorylated and activated through a three-tiered MEK mode via cell surface receptors stimulated by growth factors or cytokines. The phosphorylated ERK1/2 level is usually increased after cerebral ischemia/reperfusion, but whether an increase in ERK1/2 phosphorylation is protective or detrimental is highly debatable. Much of the support for ERK1/2's role as a neuroprotectant against stroke stems from its apparent involvement in the beneficial effects of growth factors, estrogen, preconditioning, and hypothermia on the ischemic brain. Conversely, evidence supporting the detrimental effects of ERK1/2 activity is derived from its activation promoting inflammation and oxidative stress and its inhibition reducing ischemic damage. The dual potential of ERK1/2 actions in the ischemic brain is likely related to its responses to a diverse array of agonists and cell surface receptors. Plausibly, the ERK1/2 activity generated by cytokines and free radicals or other inflammatory factors after stroke may worsen ischemic damage, whereas the ERK1/2 activity produced by exogenous growth factors, estrogen, and preconditioning favors neuroprotection. Future experiments should be conducted to optimize the protective effect of ERK1/2 while blocking its detrimental actions.

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MEK1/2 inhibition attenuates vascular ETA and ETB receptor alterations after cerebral ischaemia

Abstract: Background and Purpose

Cited by 50 publications

References 44 publications

Vascular plasticity in cerebrovascular disorders

Vascular plasticity in cerebrovascular disorders

Secondhand smoke exposure induces Raf/ERK/MAPK-mediated upregulation of cerebrovascular endothelin ETA receptors

Dual roles of the MAPK/ERK1/2 cell signaling pathway after stroke

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