Aortic remodeling after transverse aortic constriction in mice is attenuated with AT1 receptor blockade.
Aortic remodeling after transverse aortic constriction in mice is attenuated with AT1 receptor blockade.
复制标题
小鼠横向主动脉收缩后主动脉重塑被AT1受体阻断减弱。
DOI：
10.1161/atvbaha.113.301624
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发表时间：
2013-09
期刊：
影响因子：
--
通讯作者：
Milewicz DM
中科院分区：
文献类型：
--
作者：
Kuang SQ;Geng L;Prakash SK;Cao JM;Guo S;Villamizar C;Kwartler CS;Peters AM;Brasier AR;Milewicz DM
虽然高血压是胸主动脉疾病最常见的危险因素，但尚不清楚升主动脉上的压力增加如何导致主动脉瘤。我们研究的作用，血管紧张素Ⅱ 1型（AT 1）受体激活升主动脉重塑反应增加的生物力学力量使用横向主动脉缩窄（TAC）小鼠模型。TAC后2周，生物力学压力增加导致升主动脉扩张，主动脉壁增厚和中膜肥厚。TAC上行动脉中显著的外膜增生和炎症反应伴随着外膜胶原蛋白增加、炎症和增殖标志物升高以及由于肌成纤维细胞和巨噬细胞积聚而导致的细胞密度增加。氯沙坦治疗显著阻断TAC诱导的血管炎症和巨噬细胞积聚。然而，氯沙坦只能部分阻止TAC诱导的外膜增生、胶原积聚和升主动脉扩张。氯沙坦可有效阻断TAC上行动脉中层Tgfb 2表达和磷酸化Smad 2染色的增加。与此相反，增加Tgfb 1的表达和外膜磷酸化Smad 2染色仅部分衰减氯沙坦。此外，氯沙坦显著阻断TAC升主动脉中Erk活化和ROS产生。使用氯沙坦抑制AT 1受体可显著减弱与TAC相关的血管重塑，但不能完全阻断TGF- β1表达增加、外膜Smad 2信号传导和胶原积聚。这些结果有助于描述TAC后主动脉TGF-β信号传导依赖于和不依赖于AT 1受体。
Although hypertension is the most common risk factor for thoracic aortic diseases, it is not understood how increased pressures on the ascending aorta lead to aortic aneurysms. We investigated the role of Ang II type 1 (AT1) receptor activation in ascending aortic remodeling in response to increased biomechanical forces using a transverse aortic constriction (TAC) mouse model. Two weeks after TAC, the increased biomechanical pressures led to ascending aortic dilatation, aortic wall thickening and medial hypertrophy. Significant adventitial hyperplasia and inflammatory responses in TAC ascending aortas were accompanied by increased adventitial collagen, elevated inflammatory and proliferative markers, and increased cell density due to accumulation of myofibroblasts and macrophages. Treatment with losartan significantly blocked TAC induced vascular inflammation and macrophage accumulation. However, losartan only partially prevented TAC induced adventitial hyperplasia, collagen accumulation and ascending aortic dilatation. Increased Tgfb2 expression and phosphorylated-Smad2 staining in the medial layer of TAC ascending aortas was effectively blocked with losartan. In contrast, the increased Tgfb1 expression and adventitial phospho-Smad2 staining were only partially attenuated by losartan. In addition, losartan significantly blocked Erk activation and ROS production in the TAC ascending aorta. Inhibition of the AT1 receptor using losartan significantly attenuated the vascular remodeling associated with TAC but did not completely block the increased TGF- β1 expression, adventitial Smad2 signaling and collagen accumulation. These results help to delineate the aortic TGF-β signaling that is dependent and independent of the AT1 receptor after TAC.