Human cerebrovascular contractile receptors are upregulated via a B-Raf/MEK/ERK-sensitive signaling pathway.
Human cerebrovascular contractile receptors are upregulated via a B-Raf/MEK/ERK-sensitive signaling pathway.
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DOI：
10.1186/1471-2202-12-5
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发表时间：
2011-01-11
期刊：
影响因子：
2.4
通讯作者：
Edvinsson L
中科院分区：
文献类型：
--
作者：
Ahnstedt H;Säveland H;Nilsson O;Edvinsson L
脑缺血导致缺血区血管壁上收缩的脑血管受体如5-羟色胺1B(5-HT1B)、血管紧张素II 1型(AT1)和内皮素B型(ETB)受体迅速增加，进一步损害局部血流，加重组织损伤。这种受体的上调是通过激活丝裂原激活的蛋白激酶途径来实现的。因此，我们假设了B-Raf的重要作用，它是该通路中的第一个信号分子。为了验证我们的假设，在没有或存在B-Raf抑制剂SB-386023或SB-590885的情况下，将人的大脑动脉在37℃下孵育48小时。用肌图仪和单个受体的蛋白表达来评估收缩特性，并用免疫组织化学方法检测活化的磷酸化B-Raf(p-B-Raf)。SB-590885显著减少5-HT1B、AT1和ETB受体介导的收缩，SB-386023的作用较小。SB-590885处理后，AT1受体免疫反应性明显降低。Sb-590885和Sb-386023处理可减弱培养引起的p-B-Raf免疫反应增强。B-Raf信号在器官培养后血管收缩受体表达改变中起关键作用。因此，特异性靶向B-Raf可能是一种通过阻止先前观察到的平滑肌细胞收缩受体上调来减轻脑缺血后组织损伤的新方法。
Cerebral ischemia results in a rapid increase in contractile cerebrovascular receptors, such as the 5-hydroxytryptamine type 1B (5-HT1B), angiotensin II type 1 (AT1), and endothelin type B (ETB) receptors, in the vessel walls within the ischemic region, which further impairs local blood flow and aggravates tissue damage. This receptor upregulation occurs via activation of the mitogen-activated protein kinase pathway. We therefore hypothesized an important role for B-Raf, the first signaling molecule in the pathway. To test our hypothesis, human cerebral arteries were incubated at 37°C for 48 h in the absence or presence of a B-Raf inhibitor: SB-386023 or SB-590885. Contractile properties were evaluated in a myograph and protein expression of the individual receptors and activated phosphorylated B-Raf (p-B-Raf) was evaluated immunohistochemically. 5-HT1B, AT1, and ETB receptor-mediated contractions were significantly reduced by application of SB-590885, and to a smaller extent by SB-386023. A marked reduction in AT1 receptor immunoreactivity was observed after treatment with SB-590885. Treatment with SB-590885 and SB-386023 diminished the culture-induced increase of p-B-Raf immunoreactivity. B-Raf signaling has a key function in the altered expression of vascular contractile receptors observed after organ culture. Therefore, specific targeting of B-Raf might be a novel approach to reduce tissue damage after cerebral ischemia by preventing the previously observed upregulation of contractile receptors in smooth muscle cells.
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DOI：
10.1152/ajpheart.00857.2007
发表时间：
2007-12-01
影响因子：
4.8
作者：
Ansar, Saema;Vikman, Petter;Edvinsson, Lars
通讯作者：
Edvinsson, Lars
影响因子：
2
作者：
Henriksson, Marie;Stenman, Emelie;Edvinsson, Lars
通讯作者：
Edvinsson, Lars
影响因子：
2.4
作者：
Maddahi, Aida;Edvinsson, Lars
通讯作者：
Edvinsson, Lars
影响因子：
4.8
作者：
Nilsson, T;Cantera, L;Edvinsson, L
通讯作者：
Edvinsson, L
影响因子：
20.1
作者：
MULVANY, MJ;HALPERN, W
通讯作者：
HALPERN, W