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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Endothelial Notch4 signaling induces hallmarks of brain arteriovenous malformations in mice
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Endothelial Notch4 signaling induces hallmarks of brain arteriovenous malformations in mice

机译：内皮Notch4信号转导小鼠脑动静脉畸形的标志

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摘要

Brain arteriovenous malformations (BAVMs) can cause devastating stroke in young people and contribute to half of all hemorrhagic stroke in children. Unfortunately, the pathogenesis of BAVMs is unknown. In this article we show that activation of Notch signaling in the endothelium during brain development causes BAVM in mice. We turned on constitutively active Notch4 (int3) expression in endothelial cells from birth by using the tetracycline-regulatable system. All mutants developed hallmarks of BAVMs, including cerebral arteriovenous shunting and vessel enlargement, by 3 weeks of age and died by 5 weeks of age. Twenty-five percent of the mutants showed signs of neurological dysfunction, including ataxia and seizure. Affected mice exhibited hemorrhage and neu-ronal cell death within the cerebral cortex and cerebellum. Strikingly, int3 repression resolved ataxia and reversed the disease progression, demonstrating that int3 is not only sufficient to induce, but also required to sustain the disease. We show that int3 expression results in widespread enlargement of the microvascu-lature, which coincided with a reduction in capillary density, linking vessel enlargement to Notch's known function of inhibiting vessel sprouting. Our data suggest that the Notch pathway is a molecular regulator of BAVM pathogenesis in mice, and offer hope that their regression might be possible by targeting the causal molecular lesion.
机译：脑动静脉畸形（BAVM）可能在年轻人中造成毁灭性的中风，并造成儿童出血性中风的一半。不幸的是，BAVMs的发病机制尚不清楚。在本文中，我们证明了在大脑发育过程中内皮中Notch信号的激活会引起小鼠BAVM。通过使用四环素调节系统，我们从出生开始就在内皮细胞中组成型活跃的Notch4（int3）表达。所有突变体在3周龄时都表现出BAVM的特征，包括脑动静脉分流和血管扩张，并在5周龄时死亡。 25％的突变体表现出神经功能障碍的迹象，包括共济失调和癫痫发作。患病小鼠在大脑皮层和小脑内表现出出血和神经​​元细胞死亡。令人惊讶的是，int3抑制解决了共济失调，并逆转了疾病进展，表明int3不仅足以诱导疾病，而且还足以维持疾病。我们显示int3表达导致微血管的广泛扩大，这与毛细血管密度的降低相吻合，将血管的扩大与Notch抑制血管发芽的已知功能联系起来。我们的数据表明，Notch途径是小鼠BAVM发病机制的分子调节剂，并希望通过靶向病因分子病变使它们的消退成为可能。

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