Overexpression of transforming growth factor-β1 stabilizes already-formed aortic aneurysms -: A first approach to induction of functional healing by endovascular gene therapy
Overexpression of transforming growth factor-β1 stabilizes already-formed aortic aneurysms -: A first approach to induction of functional healing by endovascular gene therapy
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DOI：
10.1161/circulationaha.104.523357
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发表时间：
2005-08-16
期刊：
影响因子：
37.8
通讯作者：
Allaire, E
中科院分区：
文献类型：
--
作者：
Dai, JP;Losy, F;Allaire, E
背景-细胞对转化生长因子-β1(转化生长因子-β1)的反应因组织环境的不同而不同。转化生长因子-β1是一种具有愈合潜力的多潜能细胞因子。我们评价了血管内基因治疗对已经受到炎症和蛋白分解损伤的腹主动脉瘤(AAA)的稳定作用的能力。方法和结果-在已经发展起来的实验性AAA中，在血管内注射编码突变形式的猴的TGF-β1的腺病毒载体后，以及在使用人动脉粥样硬化的AAA片段与重组活性的TGF-β1孵育的外植体模型中，已经发展起来的实验性AAA获得了活性的TGF-β1的过度表达。血管内基因治疗的瞬时外源性的TGF-β1的过度表达，随后是内源性的大鼠的转化生长因子-β1的诱导。在实验性的腹主动脉瘤中，活性的转化生长因子-β1的过度表达与直径的稳定、中层弹性蛋白、中层弹性蛋白的保持有关。减少单核巨噬细胞和T淋巴细胞的渗透，减少基质金属蛋白酶-2和-9的表达，这在移植模型中也可以观察到，血栓和壁上都有。伴随着破坏过程的下调，活跃的转化生长因子-β1的过度表达引发了腔内重建，血栓被富含血管平滑肌细胞、胶原和弹性蛋白的起始物取代。结论：局部的转化生长因子-β1在短暂的外源性过度表达后自我诱导，重建因炎症和蛋白分解而改变的扩张的主动脉，并恢复其承受动脉压力的能力而不需要进一步扩张。这一首次证明了通过传递单一的多潜能自我促进基因来稳定扩张的AAA，支持了血管内基因治疗应该被考虑用于治疗动脉瘤的观点。
Background-The cell response to transforming growth factor-beta 1 (TGF-beta 1), a multipotent cytokine with healing potential, varies according to tissue context. We have evaluated the ability of TGF-beta 1 overexpression by endovascular gene therapy to stabilize abdominal aortic aneurysms (AAAs) already injured by inflammation and proteolysis.Methods and Results-Active TGF-beta 1 overexpression was obtained in already-developed experimental AAAs in rats after endovascular delivery of an adenoviral construct encoding for a mutated form of active simian TGF-beta 1 and in an explant model using human atherosclerotic AAA fragments incubated with recombinant active TGF-beta 1. Transient exogenous TGF-beta 1 overexpression by endovascular gene delivery was followed by induction of endogenous rat TGF-beta 1. Overexpression of active TGF-beta 1 in experimental AAAs was associated with diameter stabilization, preservation of medial elastin, decreased infiltration of monocyte-macrophages and T lymphocytes, and a decrease in matrix metalloproteinase-2 and -9, which was also observed in the explant model, in both thrombus and wall. In parallel with downregulation of the destructive process, active TGF-beta 1 overexpression triggered endoluminal reconstruction, replacing the thrombus by a vascular smooth muscle cell-, collagen-, and elastin-rich intima.Conclusions-Local TGF-beta 1 self-induction after transient exogenous overexpression reprograms dilated aortas altered by inflammation and proteolysis and restores their ability to withstand arterial pressure without further dilation. This first demonstration of stabilization of expanding AAAs by delivery of a single multipotent self-promoting gene supports the view that endovascular gene therapy should be considered for treatment of aneurysms.