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首页> 外文期刊>Biology Open >Changing topographic Hox expression in blood vessels results in regionally distinct vessel wall remodeling
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Changing topographic Hox expression in blood vessels results in regionally distinct vessel wall remodeling

机译：血管中地形Hox表达的变化会导致不同区域的血管壁重塑

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The distinct topographic Hox expression patterns observed in vascular smooth muscle cells (VSMCs) of the adult cardiovascular system suggest that these transcriptional regulators are critical for maintaining region-specific physiological properties of blood vessels. To test this proposition, we expanded the vascular Hoxc11 expression domain normally restricted to the lower limbs by utilizing an innovative integrated tetracycline regulatory system and Transgelin promoter elements to induce Hoxc11 expression universally in VSMCs of transgenic mice. Ectopic Hoxc11 expression in carotid arteries, aortic arch and descending aorta resulted in drastic vessel wall remodeling involving elastic laminae fragmentation, medial smooth muscle cell loss, and intimal lesion formation. None of these alterations were observed upon induction of Hoxc11 transgene expression in the femoral artery, i.e. the natural Hoxc11 activity domain, although this vessel was greatly enlarged, comparable to the topographically restricted vascular changes seen in Hoxc11?/? mice. To begin defining Hoxc11 -controlled pathways of vascular remodeling, we performed immunolabeling studies in conjunction with co-transfection and chromatin immunoprecipitation (ChIP) assays using mouse vascular smooth muscle (MOVAS) cells. The results suggest direct transcriptional control of two members of the matrix metalloproteinase (Mmp) family, including Mmp2 and Mmp9 that are known as key players in the inception and progression of vascular remodeling events. In summary, the severe vascular abnormalities resulting from the induced dysregulated expression of a Hox gene with regional vascular patterning functions suggest that proper Hox function and regulation is critical for maintaining vascular functional integrity.
机译：在成人心血管系统的血管平滑肌细胞（VSMC）中观察到的独特的地形Hox表达模式表明，这些转录调节因子对于维持特定区域的血管生理特性至关重要。为了测试这一命题，我们利用创新的整合四环素调节系统和Transgelin启动子元件，在转基因小鼠的VSMC中普遍诱导Hoxc11表达，从而扩展了通常限于下肢的血管Hoxc11表达域。异位Hoxc11在颈动脉，主动脉弓和降主动脉中的表达导致剧烈的血管壁重塑，涉及弹性薄片断裂，内侧平滑肌细胞丢失和内膜病变形成。诱导股动脉Hoxc11转基因表达，即天然Hoxc11活性结构域时，没有观察到这些改变，尽管该血管大大扩大了，可与Hoxc11α/β中受地形限制的血管变化相比。老鼠。为了开始定义Hoxc11控制的血管重塑途径，我们使用小鼠血管平滑肌（MOVAS）细胞结合共转染和染色质免疫沉淀（ChIP）分析进行了免疫标记研究。结果表明，基质金属蛋白酶（Mmp）家族的两个成员（包括Mmp2和Mmp9）的直接转录控制被称为血管重塑事件的发生和发展的关键参与者。总之，由具有区域性血管模式功能的Hox基因的诱导表达失调导致的严重血管异常提示，正确的Hox功能和调节对于维持血管功能完整性至关重要。

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