Age-related Notch-4 quiescence is associated with altered wall remodeling during vein graft adaptation.
Age-related Notch-4 quiescence is associated with altered wall remodeling during vein graft adaptation.
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DOI：
10.1016/j.jss.2011.06.036
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发表时间：
2011-11
期刊：
影响因子：
--
通讯作者：
Dardik A
中科院分区：
文献类型：
--
作者：
Kondo Y;Muto A;Kudo FA;Model L;Eghbalieh S;Chowdhary P;Dardik A
衰老与血管生物学的特定机制之间的联系尚不清楚。我们之前的研究表明，衰老与静脉移植物壁厚增加有关，这一过程涉及VEGF-Delta/Notch-ephrin/Eph级联反应。因此，我们研究了在静脉移植物适应过程中，dl4或Notch-4是否根据年龄差异表达。6月龄和24月龄Fischer 344大鼠分别行静脉移植。采用实时荧光定量PCR法分析基因表达，免疫荧光法观察Dll-4和Notch-4的分布。与青壮年大鼠相比，老龄大鼠移植静脉中Dll-4和Notch-4的表达降低。dl -4和Notch-4均分布在静脉移植物内皮和外外膜中，年龄较大的静脉移植物外外膜中含量减少。与年轻成人相比，老年静脉eNOS膜的靶向性和小泡蛋白-1的共定位降低，eNOS蛋白的表达也降低。在幼龄和老年动物之间的交换模型中，异质静脉移植物（YoAg和AgYo）与幼龄（YoYo）对照相比，显示出明显更厚的新内膜，并且外膜中notch -4阳性细胞减少，而dll -4阳性细胞减少。空气剥去内皮的静脉移植物对动脉环境没有任何适应性，并且在3周时缺乏Dll-4和Notch-4的表达。在静脉移植物适应动脉环境的过程中，dl -4和Notch-4的表达在老年背景下下调，而在年轻背景下则不下调。Notch-4缺失与新生内膜衰减缺失有关。delta-Notch信号通路在静脉移植物适应过程中可能是活跃的。
The link of aging to specific mechanisms of vascular biology is not well understood. We have previously shown that aging is associated with increased vein graft wall thickness and that this process involves the VEGF-Delta/Notch-ephrin/Eph cascade. Therefore we examined whether Dll-4 or Notch-4 are differentially expressed, according to age, during vein graft adaptation. Vein grafts were performed in 6-month and 24-month Fischer 344 rats. Gene expression was analyzed by quantitative real-time PCR, and the distribution of Dll-4 and Notch-4 was observed by immunofluorescence. The expression of Dll-4 and Notch-4 was reduced in vein grafts performed in aged rats compared to the expression in young adult rats. Both Dll-4 and Notch-4 were distributed in vein graft endothelium as well as the outer adventitia, with reduced amounts in the outer adventitia of aged vein grafts. Aged veins had reduced eNOS membrane targeting and colocalization with caveolin-1 as well as reduced eNOS protein expression in comparison to young adult veins. In an exchange model between young and aged animals, heterogeneous vein grafts (YoAg and AgYo) showed significantly thicker neointima compared to young (YoYo) controls, and had Notch-4-positive cells, but not Dll-4-positive cells, diminished in the adventitia. Vein grafts that were air-denuded of endothelium did not show any adaptation to the arterial environment and also lacked both Dll-4 and Notch-4 expression at 3 weeks. During vein graft adaptation to the arterial environment, both Dll-4 and Notch-4 expression are down-regulated in an aged, but not a young, background. Loss of Notch-4 is associated with loss of attenuation of neointima. The delta-Notch signaling pathway may be active during vein graft adaptation.
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