Endothelial Notch signaling is upregulated in human brain arteriovenous malformations and a mouse model of the disease.
Endothelial Notch signaling is upregulated in human brain arteriovenous malformations and a mouse model of the disease.
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DOI：
10.1038/labinvest.2009.62
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发表时间：
2009-09
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影响因子：
--
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脑动静脉畸形（BAVMs）可引起致命的出血性中风，目前尚无有效的治疗方法。这种疾病的细胞和分子基础在很大程度上是未知的。我们之前的研究表明，内皮中组成型活性Notch4受体的表达引发并维持了小鼠BAVM的特征，从而建立了该疾病的小鼠模型。我们的工作提示Notch通路可能是BAVM发病的关键分子介质。在这里，我们研究了Notch激活上调参与人类BAVM发病机制的假设。我们通过免疫荧光检测了Notch下游靶点Hes1在人bavm内皮中的表达，结果显示，相对于尸检或手术活检对照组，Hes1的表达水平均有所增加。然后，我们使用Notch1受体活化形式的抗体分析受体活性，发现活性水平增加。这些发现提示Notch的激活可能促进了BAVM的发展甚至维持。我们还检测到由组成型活性Notch4诱导的小鼠BAVM模型中Hes1和Notch1表达的增加，证明了小鼠模型与人类疾病之间的分子相似性。我们的工作表明Notch信号的激活是BAVM发病机制的重要候选分子，并进一步验证了我们的动物模型为研究疾病的进展和消退提供了一个平台。
Brain arteriovenous malformations (BAVMs) can cause lethal hemorrhagic stroke and have no effective treatment. The cellular and molecular basis for this disease is largely unknown. We have previously shown that expression of constitutively-active Notch4 receptor in the endothelium elicits and maintains the hallmarks of BAVM in mice, thus establishing a mouse model of the disease. Our work suggested that Notch pathway could be a critical molecular mediator of BAVM pathogenesis. Here, we investigated the hypothesis that upregulated Notch activation contributes to the pathogenesis of human BAVM. We examined expression of the canonical Notch downstream target Hes1 in the endothelium of human BAVMs by immunofluorescence, and showed increased levels relative to either autopsy or surgical biopsy controls. We then analyzed receptor activity using an antibody to the activated form of the Notch1 receptor, and found increased levels of activity. These findings suggest that Notch activation may promote the development and even maintenance of BAVM. We also detected increases in Hes1 and activated Notch1 expression in our mouse model of BAVM induced by constitutively-active Notch4, demonstrating molecular similarity between the mouse model and the human disease. Our work suggests that activation of Notch signaling is an important molecular candidate in BAVM pathogenesis and further validates that our animal model provides a platform to study the progression as well as the regression of the disease.
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DOI：
10.1083/jcb.200702009
发表时间：
2007-07-30
期刊：
The Journal of cell biology
影响因子：
--
作者：
Geffers I;Serth K;Chapman G;Jaekel R;Schuster-Gossler K;Cordes R;Sparrow DB;Kremmer E;Dunwoodie SL;Klein T;Gossler A
通讯作者：
Gossler A
影响因子：
8.3
作者：
ApSimon, HT;Reef, H;Popovic, EA
通讯作者：
Popovic, EA
影响因子：
20.1
作者：
Hashimoto, T;Lam, T;Young, WL
通讯作者：
Young, WL
影响因子：
2.7
作者：
Arthur, HM;Ure, J;Diamond, AG
通讯作者：
Diamond, AG
影响因子：
56.9
作者：
Hirata, H;Yoshiura, S;Kageyama, R
通讯作者：
Kageyama, R