Vascular Biology and Hypertension Program, Division of Cardiovascular Disease, Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama; and.
Am J Physiol Heart Circ Physiol. 2013 Oct 15;305(8):H1256-64. doi: 10.1152/ajpheart.00132.2013. Epub 2013 Aug 16.
Endothelial dysfunction is prevalent in chronic kidney disease. This study tested the hypothesis that transfusion of rat aortic endothelial cells (ECs) ameliorates endothelial dysfunction in a rat model of chronic kidney disease. Male Sprague-Dawley rats underwent sham surgery or 5/6 nephrectomy (Nx). Five weeks after Nx, EC (1.5 × 10(6) cells/rat) or vehicle were transfused intravenously. One week later, vascular reactivity of mesenteric artery was assessed on a wire myograph. Sensitivity of endothelium-dependent relaxation to acetylcholine and maximum vasodilation were impaired by Nx and improved by EC transfusion. Using selective pharmacological nitric oxide synthase isoform inhibitors, we demonstrated that the negative effect of Nx on endothelial function and rescue by EC transfusion are, at least in part, endothelial nitric oxide synthase mediated. Plasma asymmetric dimethylarginine was increased by Nx and decreased by EC transfusion, whereas mRNA expression of dimethylarginine dimethylaminohydrolases 1 (DDAH1) was decreased by Nx and restored by EC transfusion. Immunohistochemical staining confirmed that local expression of DDAH1 is decreased by Nx and increased by EC transfusion. In conclusion, EC transfusion attenuates Nx-induced endothelium-dependent vascular dysfunction by regulating DDAH1 expression and enhancing endothelial nitric oxide synthase activity. These results suggest that EC-based therapy could provide a novel therapeutic strategy to improve vascular function in chronic kidney disease.
内皮功能障碍在慢性肾脏病中很常见。本研究检验了这样一个假设，即输注大鼠主动脉内皮细胞（EC）可改善慢性肾脏病大鼠模型中的内皮功能障碍。雄性 Sprague-Dawley 大鼠接受假手术或 5/6 肾切除术（Nx）。Nx 后 5 周，静脉输注 EC（1.5×10^6 细胞/大鼠）或载体。1 周后，在测压肌描记器上评估肠系膜动脉的血管反应性。乙酰胆碱诱导的内皮依赖性松弛的敏感性和最大血管扩张均被 Nx 损害，而 EC 输注可改善这些功能。使用选择性的一氧化氮合酶同工酶抑制剂，我们证明了 Nx 对内皮功能的负性影响以及 EC 输注的挽救作用至少部分是通过内皮型一氧化氮合酶介导的。Nx 增加了血浆不对称二甲基精氨酸，而 EC 输注降低了其含量，而 Nx 降低了二甲基精氨酸二甲氨基水解酶 1（DDAH1）的 mRNA 表达，而 EC 输注则恢复了其表达。免疫组织化学染色证实，Nx 降低了局部 DDAH1 的表达，而 EC 输注增加了其表达。总之，EC 输注通过调节 DDAH1 表达和增强内皮型一氧化氮合酶活性来减轻 Nx 诱导的内皮依赖性血管功能障碍。这些结果表明，基于 EC 的治疗可能为改善慢性肾脏病中的血管功能提供一种新的治疗策略。
