Lady Davis Institute for Medical Research.
Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, #B-127, 3755 Côte-Ste-Catherine Road, Montreal, QC H3T 1E2, Canada.
Cardiovasc Res. 2017 Dec 1;113(14):1753-1762. doi: 10.1093/cvr/cvx115.
Matrix metalloproteinases (MMPs) have been implicated in the development of hypertension in animal models and humans. Mmp2 deletion did not change Ang II-induced blood pressure (BP) rise. However, whether Mmp2 knockout affects angiotensin (Ang) II-induced vascular injury has not been tested. We sought to determine whether Mmp2 knockout will prevent Ang II-induced vascular injury.
A fourteen-day Ang II infusion (1000 ng/kg/min, SC) increased systolic BP, decreased vasodilatory responses to acetylcholine, induced mesenteric artery (MA) hypertrophic remodelling, and enhanced MA stiffness in wild-type (WT) mice. Ang II enhanced aortic media and perivascular reactive oxygen species generation, aortic vascular cell adhesion molecule-1 and monocyte chemotactic protein-1 expression, perivascular monocyte/macrophage and T cell infiltration, and the fraction of spleen activated CD4+CD69+ and CD8+CD69+ T cells, and Ly-6Chi monocytes. Study of intracellular signalling showed that Ang II increased phosphorylation of epidermal growth factor receptor and extracellular-signal-regulated kinase 1/2 in vascular smooth muscle cells isolated from WT mice. All these effects were reduced or prevented by Mmp2 knockout, except for systolic BP elevation. Ang II increased Mmp2 expression in immune cells infiltrating the aorta and perivascular fat. Bone marrow (BM) transplantation experiments revealed that in absence of MMP2 in immune cells, Ang II-induced BP elevation was decreased, and that when MMP2 was deficient in either immune or vascular cells, Ang II-induced endothelial dysfunction was blunted.
Mmp2 knockout impaired Ang II-induced vascular injury but not BP elevation. BM transplantation revealed a role for immune cells in Ang II-induced BP elevation, and for both vascular and immune cell MMP2 in Ang II-induced endothelial dysfunction.
基质金属蛋白酶（MMPs）已被牵涉到动物模型和人类高血压的发展中。Mmp2 缺失并没有改变 Ang II 引起的血压升高。然而，Mmp2 敲除是否会影响血管紧张素（Ang）II 引起的血管损伤尚未得到测试。我们试图确定 Mmp2 敲除是否会预防 Ang II 引起的血管损伤。
十四天 Ang II 输注（1000ng/kg/min，SC）增加了收缩压，降低了对乙酰胆碱的血管舒张反应，引起肠系膜动脉（MA）肥厚性重塑，并增强了野生型（WT）小鼠的 MA 僵硬。Ang II 增强了主动脉中层和血管周围活性氧的产生，主动脉血管细胞黏附分子-1 和单核细胞趋化蛋白-1 的表达，血管周围单核细胞/巨噬细胞和 T 细胞浸润，以及脾脏激活的 CD4+CD69+和 CD8+CD69+T 细胞和 Ly-6Chi 单核细胞的分数。细胞内信号研究表明，Ang II 增加了从 WT 小鼠分离的血管平滑肌细胞中表皮生长因子受体和细胞外信号调节激酶 1/2 的磷酸化。除了收缩压升高之外，所有这些效应都被 Mmp2 敲除所减少或预防。Ang II 增加了浸润主动脉和血管周围脂肪的免疫细胞中的 Mmp2 表达。骨髓（BM）移植实验表明，在免疫细胞中缺乏 MMP2 时，Ang II 引起的血压升高降低，而当 MMP2 在免疫或血管细胞中缺乏时，Ang II 引起的内皮功能障碍减弱。
Mmp2 敲除损害了 Ang II 引起的血管损伤，但没有损害血压升高。BM 移植揭示了免疫细胞在 Ang II 引起的血压升高中的作用，以及血管和免疫细胞 MMP2 在 Ang II 引起的内皮功能障碍中的作用。
