Defining the critical hypoxic threshold that promotes vascular remodeling in the brain.
Defining the critical hypoxic threshold that promotes vascular remodeling in the brain.
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DOI：
10.1016/j.expneurol.2014.10.007
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发表时间：
2015-01
影响因子：
5.3
通讯作者：
Milner, Richard
中科院分区：
文献类型：
--
作者：
Boroujerdi, Amin;Milner, Richard
关键词：
在动物模型中，低氧预处理赋予对随后的神经损伤的保护，部分通过广泛的血管重塑反应介导。鉴于这种效应的治疗潜力，本研究的目的是建立缺氧水平与脑血管建模程度之间的剂量-反应关系，并确定促进重塑的最轻度缺氧水平。将小鼠暴露于不同水平的连续缺氧（8- 21%O2）7天，然后评价血管重塑的几个方面，包括内皮增殖、总血管面积、动脉生成和纤连蛋白/α5β1整合素表达。对于大多数事件，刺激重塑的缺氧阈值水平为12- 13%O2。有趣的是，许多参数显示出双相剂量-反应曲线，在10%O2时达到峰值水平，但此后下降。在12- 13%O2范围内的进一步分析表明，血管重塑通过两种不同的机制发生：（i）内皮增生，由13%O2的缺氧阈值触发，导致毛细血管生长增加，和（ii）内皮肥大，由12%O2的更严重的缺氧阈值触发，导致大血管扩张和动脉生成。总之，这些结果定义了脑血管重塑的缺氧阈值，并指出了介导这一过程的两种独立机制。
In animal models, hypoxic pre-conditioning confers protection against subsequent neurological insults, mediated in part through an extensive vascular remodeling response. In light of the therapeutic potential of this effect, the goal of this study was to establish the dose-response relationship between level of hypoxia and the extent of cerebrovascular modeling, and to define the mildest level of hypoxia that promotes remodeling. Mice were exposed to different levels of continuous hypoxia (8-21% O2) for seven days before several aspects of vascular remodeling were evaluated, including endothelial proliferation, total vascular area, arteriogenesis, and fibronectin/α5β1 integrin expression. For most events, the threshold level of hypoxia that stimulated remodeling was 12-13% O2. Interestingly, many parameters displayed a biphasic dose-response curve, with peak levels attained at 10% O2, but declined thereafter. Further analysis in the 12-13% O2 range revealed that vascular remodeling occurs by two separate mechanisms: (i) endothelial hyperplasia, triggered by a hypoxic threshold of 13% O2, which leads to increased capillary growth, and (ii) endothelial hypertrophy, triggered by a more severe hypoxic threshold of 12% O2, which leads to expansion of large vessels and arteriogenesis. Taken together, these results define the hypoxic thresholds for vascular remodeling in the brain, and point to two separate mechanisms mediating this process.
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