Interaction between alk1 and blood flow in the development of arteriovenous malformations
Interaction between alk1 and blood flow in the development of arteriovenous malformations
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DOI：
10.1242/dev.060467
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发表时间：
2011-04-15
期刊：
影响因子：
4.6
通讯作者：
Roman, Beth L.
中科院分区：
文献类型：
--
作者：
Corti, Paola;Young, Sarah;Roman, Beth L.
动静脉畸形(AVM)是动脉和静脉之间脆弱的直接连接，发生在血管生成活跃的时期。为了了解动静脉畸形的病因和血流在其发育中的作用，我们分析了携带激活素受体样激酶I(ALK1)突变的斑马鱼胚胎中动静脉动静脉畸形的发育，激活素受体样激酶I(ALK1)编码转化生长因子β家族I型受体，与人类血管疾病遗传性出血性毛细血管扩张症(HHT2)有关。我们的分析表明，动脉管径的增加，部分源于细胞数量的增加和部分细胞密度的降低，先于动静脉畸形的发展，动静脉动静脉连接的扩大和稳定代表着正常的瞬时动静脉连接的扩大和稳定。虽然最初内皮细胞数量的增加与血流无关，但后来的增加以及动静脉动静脉畸形取决于血流。此外，我们还证明了ALK1的表达需要血液流动，尽管剪切力水平正常，但在ALK1突变的动脉内皮细胞中，一些与血流反应的基因是失调的。综上所述，我们的结果表明，Alk1在将血流动力转换为限制新生血管管径所需的生化信号方面发挥了作用，并支持了HHT相关AVM发展的新的两步模型，在该模型中，病理性动脉增大和随之而来的血流变化引发了一种血流依赖的适应性反应，包括保留正常的瞬时动静脉连接，从而产生AVM。
Arteriovenous malformations (AVMs) are fragile direct connections between arteries and veins that arise during times of active angiogenesis. To understand the etiology of AVMs and the role of blood flow in their development, we analyzed AVM development in zebrafish embryos harboring a mutation in activin receptor-like kinase I (alk1), which encodes a TGF beta family type I receptor implicated in the human vascular disorder hereditary hemorrhagic telangiectasia type 2 (HHT2). Our analyses demonstrate that increases in arterial caliber, which stem in part from increased cell number and in part from decreased cell density, precede AVM development, and that AVMs represent enlargement and stabilization of normally transient arteriovenous connections. Whereas initial increases in endothelial cell number are independent of blood flow, later increases, as well as AVMs, are dependent on flow. Furthermore, we demonstrate that alk1 expression requires blood flow, and despite normal levels of shear stress, some flow-responsive genes are dysregulated in alk1 mutant arterial endothelial cells. Taken together, our results suggest that Alk1 plays a role in transducing hemodynamic forces into a biochemical signal required to limit nascent vessel caliber, and support a novel two-step model for HHT-associated AVM development in which pathological arterial enlargement and consequent altered blood flow precipitate a flow-dependent adaptive response involving retention of normally transient arteriovenous connections, thereby generating AVMs.