Early events triggering delayed vasoconstrictor receptor upregulation and cerebral ischemia after subarachnoid hemorrhage

BMC Neuroscience

Lars Edvinsson¹  Ajoy Kumar Samraj¹  Carl Christian Larsen²  Sara Ellinor Johansson¹  Gro Klitgaard Povlsen¹ 

[1]Department of Clinical Experimental Research, Glostrup Research Institute, Glostrup University Hospital, Nordre Ringvej 69, Glostrup, DK 2600, Denmark

[2]Department of Neurosurgery, Glostrup University Hospital, Glostrup, Denmark

关键词: Subarachnoid hemorrhage;    Neurological outcome;    5-Hydroxytryptamine receptor;    Endothelin receptor;    Cerebral blood flow;   

Others  :  1140382
DOI  :  10.1186/1471-2202-14-34

 received in 2012-08-30, accepted in 2013-03-07,  发布年份 2013

【 摘 要 】

Background

Upregulation of vasoconstrictor receptors in cerebral arteries, including endothelin B (ET_B) and 5-hydroxytryptamine 1B (5-HT_1B) receptors, has been suggested to contribute to delayed cerebral ischemia, a feared complication after subarachnoid hemorrhage (SAH). This receptor upregulation has been shown to be mediated by intracellular signalling via the mitogen activated protein kinase kinase (MEK1/2) - extracellular regulated kinase 1/2 (ERK1/2) pathway. However, it is not known what event(s) that trigger MEK-ERK1/2 activation and vasoconstrictor receptor upregulation after SAH.

We hypothesise that the drop in cerebral blood flow (CBF) and wall tension experienced by cerebral arteries in acute SAH is a key triggering event. We here investigate the importance of the duration of this acute CBF drop in a rat SAH model in which a fixed amount of blood is injected into the prechiasmatic cistern either at a high rate resulting in a short acute CBF drop or at a slower rate resulting in a prolonged acute CBF drop.

Results

We demonstrate that the duration of the acute CBF drop is determining for a) degree of early ERK1/2 activation in cerebral arteries, b) delayed upregulation of vasoconstrictor receptors in cerebral arteries and c) delayed CBF reduction, neurological deficits and mortality. Moreover, treatment with an inhibitor of MEK-ERK1/2 signalling during an early time window from 6 to 24 h after SAH was sufficient to completely prevent delayed vasoconstrictor receptor upregulation and improve neurological outcome several days after the SAH.

Conclusions

Our findings suggest a series of events where 1) the acute CBF drop triggers early MEK-ERK1/2 activation, which 2) triggers the transcriptional upregulation of vasoconstrictor receptors in cerebral arteries during the following days, where 3) the resulting enhanced cerebrovascular contractility contribute to delayed cerebral ischemia.

【 授权许可】

   
2013 Povlsen et al.; licensee BioMed Central Ltd.

【 图 表 】

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