From the BHF Centre of Research Excellence, Division of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK (L.M.F., G.D., J.K.B., E.M., M.J.C., A.B.H., M.A.M., J.E.S., R.P.L., K.M.C.); and Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, UK (A.M., J.-M.L.).
Circulation. 2014 Jun 24;129(25):2661-72. doi: 10.1161/CIRCULATIONAHA.113.005062. Epub 2014 May 7.
Increased production of reactive oxygen species (ROS) throughout the vascular wall is a feature of cardiovascular disease states, but therapeutic strategies remain limited by our incomplete understanding of the role and contribution of specific vascular cell ROS to disease pathogenesis. To investigate the specific role of endothelial cell (EC) ROS in the development of structural vascular disease, we generated a mouse model of endothelium-specific Nox2 overexpression and tested the susceptibility to aortic dissection after angiotensin II (Ang II) infusion.
A specific increase in endothelial ROS production in Nox2 transgenic mice was sufficient to cause Ang II-mediated aortic dissection, which was never observed in wild-type mice. Nox2 transgenic aortas had increased endothelial ROS production, endothelial vascular cell adhesion molecule-1 expression, matrix metalloproteinase activity, and CD45(+) inflammatory cell infiltration. Conditioned media from Nox2 transgenic ECs induced greater Erk1/2 phosphorylation in vascular smooth muscle cells compared with wild-type controls through secreted cyclophilin A (CypA). Nox2 transgenic ECs (but not vascular smooth muscle cells) and aortas had greater secretion of CypA both at baseline and in response to Ang II stimulation. Knockdown of CypA in ECs abolished the increase in vascular smooth muscle cell Erk1/2 phosphorylation conferred by EC conditioned media, and preincubation with CypA augmented Ang II-induced vascular smooth muscle cell ROS production.
These findings demonstrate a pivotal role for EC-derived ROS in the determination of the susceptibility of the aortic wall to Ang II-mediated aortic dissection. ROS-dependent CypA secretion by ECs is an important signaling mechanism through which EC ROS regulate susceptibility of structural components of the aortic wall to aortic dissection.
血管壁中活性氧(ROS)的产生增加是心血管疾病状态的一个特征,但由于我们对特定血管细胞 ROS 在疾病发病机制中的作用和贡献的理解不完整,治疗策略仍然有限。为了研究内皮细胞(EC)ROS 在结构性血管疾病发展中的特定作用,我们生成了一种内皮细胞特异性 Nox2 过表达的小鼠模型,并测试了血管紧张素 II(Ang II)输注后发生主动脉夹层的易感性。
Nox2 转基因小鼠中内皮 ROS 产生的特异性增加足以引起 Ang II 介导的主动脉夹层,而在野生型小鼠中从未观察到这种情况。Nox2 转基因小鼠的主动脉内皮 ROS 产生增加,内皮血管细胞黏附分子-1 表达增加,基质金属蛋白酶活性增加,CD45(+)炎症细胞浸润增加。与野生型对照相比,Nox2 转基因 EC 条件培养基诱导血管平滑肌细胞中 Erk1/2 磷酸化的作用更大,这是通过分泌的亲环蛋白 A(CypA)实现的。Nox2 转基因 EC(而非血管平滑肌细胞)和主动脉在基线水平和对 Ang II 刺激的反应中均具有更高的 CypA 分泌。在 EC 中敲低 CypA 可消除由 EC 条件培养基引起的血管平滑肌细胞 Erk1/2 磷酸化的增加,并且 CypA 的预孵育增强了 Ang II 诱导的血管平滑肌细胞 ROS 产生。
这些发现表明 EC 衍生的 ROS 在确定主动脉壁对 Ang II 介导的主动脉夹层的易感性方面起着关键作用。ROS 依赖性 CypA 由 EC 分泌是一种重要的信号机制,通过该机制,EC ROS 调节主动脉壁结构成分对主动脉夹层的易感性。