Constitutively active endothelial Notch4 causes lung arteriovenous shunts in mice
Constitutively active endothelial Notch4 causes lung arteriovenous shunts in mice
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DOI：
10.1152/ajplung.00188.2009
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发表时间：
2010-02-01
影响因子：
4.9
通讯作者：
Wang, Rong A.
中科院分区：
文献类型：
--
作者：
Miniati, Doug;Jelin, Eric B.;Wang, Rong A.
Miniati D，Jelin EB，Ng J，Wu J，Carlson TR，Wu X，Looney MR，Wang RA.组成性激活的内皮Notch 4导致小鼠肺动静脉分流。美国生理学杂志肺细胞分子生理学298：L169-L177，2010年。首次发表于2009年11月20日; doi：10.1152/ajplung.00188.2009.-肺动静脉（AV）分流或畸形在几种不同的临床综合征中引起显著的发病率和死亡率。对于大多数肺AV分流患者，仍然没有最佳的治疗方法。肺AV分流的潜在分子和细胞病因学仍然难以捉摸，目前描述的动物模型不足以解决这个问题。使用四环素抑制系统，我们在成年小鼠的内皮细胞中特异性表达组成型活性Notch 4（Notch 4 *）。超过90%的小鼠在基因表达开始后6-7周发生肺水肿和呼吸功能不全并死亡。血管铸型和荧光微球分析显示受影响小鼠肺AV分流的证据。Notch 4 * 表达的停止逆转了这些病理生理效应。血管形态学评估显示肺内血管扩大、迂曲，类似动静脉畸形。通过使用全肺器官培养，我们证明了组成型活性Notch 4对肺血管系统的影响是主要的肺现象。总之，我们的研究结果表明Notch信号在维持肺血管系统中的重要性，并提供了一个新的，可靠的模型，用于研究肺动静脉分流和畸形的病理生物学。
Miniati D, Jelin EB, Ng J, Wu J, Carlson TR, Wu X, Looney MR, Wang RA. Constitutively active endothelial Notch4 causes lung arteriovenous shunts in mice. Am J Physiol Lung Cell Mol Physiol 298: L169-L177, 2010. First published November 20, 2009; doi: 10.1152/ajplung.00188.2009.-Lung arteriovenous (AV) shunts or malformations cause significant morbidity and mortality in several distinct clinical syndromes. For most patients with lung AV shunts, there is still no optimal treatment. The underlying molecular and cellular etiology for lung AV shunts remains elusive, and currently described animal models have insufficiently addressed this problem. Using a tetracycline-repressible system, we expressed constitutively active Notch4 (Notch4*) specifically in the endothelium of adult mice. More than 90% of mice developed lung hemorrhages and respiratory insufficiency and died by 6-7 wk after gene expression began. Vascular casting and fluorescent microsphere analysis showed evidence of lung AV shunts in affected mice. Cessation of Notch4* expression reversed these pathophysiological effects. Assessment of the vascular morphology revealed enlarged, tortuous vessels in the lungs that resembled arteriovenous malformations. By using whole lung organ culture, we demonstrated the effects of constitutively active Notch4 on the lung vasculature to be a primary lung phenomenon. Together, our results indicate the importance of Notch signaling in maintaining the lung vasculature and offer a new, reliable model with which to study the pathobiology of lung arteriovenous shunts and malformations.