Notch4 normalization reduces blood vessel size in arteriovenous malformations.
Notch4 normalization reduces blood vessel size in arteriovenous malformations.
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DOI：
10.1126/scitranslmed.3002670
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发表时间：
2012-01-18
影响因子：
17.1
通讯作者：
Wang RA
中科院分区：
文献类型：
--
作者：
Murphy PA;Kim TN;Lu G;Bollen AW;Schaffer CB;Wang RA
通过异常血管的高流量是许多危及生命的疾病的基础。通过分子干预安全和非侵入性地使这些血管正常化的能力有望治疗这些毁灭性的疾病。在这里，我们研究了高流量AV分流所引起的上调Notch信号通过内皮表达的组成型活性Notch4（Notch4*）。在活体小鼠中使用具有细胞分辨率的4D双光子成像，我们发现通过关闭Notch4* 使Notch信号正常化可以迅速将大口径，高流量AV分流转换为毛细血管样血管。这一过程是由血管狭窄开始的，没有内皮细胞的损失。静脉受体EphB4的恢复是一种潜在机制，因为EphB4表达在Notch正常化后恢复，并且是血管消退所需的。高流量AV分流的结构回归使分流流返回到灌注血管，逆转组织缺氧和功能障碍。我们的数据提供了直接的体内证据，证明Notch通路中的单一基因操作可以对血流动力学产生主导作用，导致AV畸形核心的高流量AV分流的安全变性。
High-flow through abnormal blood vessels underlies many life-threatening diseases. The ability to safely and non-invasively normalize these vessels by molecular intervention holds promise to treat these devastating conditions. Here we studied high-flow AV shunts caused by upregulation of Notch signaling via endothelial expression of constitutively-active Notch4 (Notch4*). Using 4D, two-photon imaging with cellular resolution in live mice, we found that normalizing Notch signaling by turning off Notch4* promptly converted large caliber, high-flow AV shunts to capillary-like vessels. The process was initiated by vessel narrowing without the loss of endothelial cells. Restoration of venous receptor EphB4 is an underlying mechanism, as EphB4 expression was recovered upon Notch normalization and required for the vessel regression. The structural regression of the high-flow AV shunts returned shunting flow to perfusing vessels, reversing tissue hypoxia and dysfunction. Our data provide direct, in vivo evidence that a single genetic manipulation in Notch pathway can exert dominant effects over hemodynamics leading to safe degeneration of the high-flow AV shunts at the core of AV Malformations.
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DOI：
10.1038/labinvest.2009.62
发表时间：
2009-09
期刊：
Laboratory investigation; a journal of technical methods and pathology
影响因子：
--
作者：
通讯作者：
--
影响因子：
14.8
作者：
Holtmaat, Anthony;Bonhoeffer, Tobias;Chow, David K.;Chuckowree, Jyoti;De Paola, Vincenzo;Hofer, Sonja B.;Huebener, Mark;Keck, Tara;Knott, Graham;Lee, Wei-Chung A.;Mostany, Ricardo;Mrsic-Flogel, Tom D.;Nedivi, Elly;Portera-Cailliau, Carlos;Svoboda, Karel;Trachtenberg, Joshua T.;Wilbrecht, Linda
通讯作者：
Wilbrecht, Linda
影响因子：
9.8
作者：
Schaffer CB;Friedman B;Nishimura N;Schroeder LF;Tsai PS;Ebner FF;Lyden PD;Kleinfeld D
通讯作者：
Kleinfeld D
影响因子：
16
作者：
Gerety, SS;Wang, HU;Anderson, DJ
通讯作者：
Anderson, DJ
DOI：
10.1152/ajplung.00188.2009
发表时间：
2010-02-01
影响因子：
4.9
作者：
Miniati, Doug;Jelin, Eric B.;Wang, Rong A.
通讯作者：
Wang, Rong A.