It is of great clinical significance to develop potential novel strategies to prevent diabetic cardiovascular complications. Endothelial progenitor cell (EPC) dysfunction is a key contributor to diabetic vascular complications. In the present study we evaluated whether low-dose nifedipine could rescue impaired EPC-mediated angiogenesis and prevent cardiovascular complications in diabetic mice. Diabetes was induced in mice by five consecutive injections of streptozotocin (STZ, 60 mg·kg⁻¹·d⁻¹, i.p.). Diabetic mice were treated with low-dose nifedipine (1.5 mg·kg⁻¹·d⁻¹, i.g.) for six weeks. Then, circulating EPCs in the peripheral blood were quantified, and bone marrow-derived EPCs (BM-EPCs) were prepared. We showed that administration of low-dose nifedipine significantly increased circulating EPCs, improved BM-EPCs function, promoted angiogenesis, and reduced the cerebral ischemic injury in diabetic mice. Furthermore, we found that low-dose nifedipine significantly increased endothelial nitric oxide synthase (eNOS) expression and intracellular NO levels, and decreased the levels of intracellular O₂^.− and thrombospondin-1/2 (TSP-1/2, a potent angiogenesis inhibitor) in BM-EPCs of diabetic mice. In cultured BM-EPCs, co-treatment with nifedipine (0.1, 1 μM) dose-dependently protected against high-glucose-induced impairment of migration, and suppressed high-glucose-induced TSP-1 secretion and superoxide overproduction. In mice with middle cerebral artery occlusion, intravenous injection of diabetic BM-EPCs treated with nifedipine displayed a greater ability to promote local angiogenesis and reduce cerebral ischemic injury compared to injection of diabetic BM-EPCs treated with vehicle, and the donor-derived BM-EPCs homed to the recipient ischemic brain. In conclusion, low-dose nifedipine can enhance EPCs’ angiogenic potential and protect against cerebral ischemic injury in diabetic mice. It is implied that chronic treatment with low-dose nifedipine may be a safe and economic manner to prevent ischemic diseases (including stroke) in diabetes.

开发预防糖尿病心血管并发症的潜在新策略具有重要的临床意义。内皮祖细胞 (EPC) 功能障碍是糖尿病血管并发症的关键因素。在本研究中，我们评估了低剂量硝苯地平是否可以挽救受损的 EPC 介导的血管生成并预防糖尿病小鼠的心血管并发症。通过连续五次注射链脲佐菌素（STZ，60 mg·kg ^-1 ·d ^-1，ip）在小鼠中诱发糖尿病。糖尿病小鼠用低剂量硝苯地平（1.5 mg·kg ^-1 ·d ^-1, ig) 六个星期。然后，对外周血中的循环 EPC 进行定量，并制备骨髓来源的 EPC（BM-EPC）。结果表明，给予低剂量硝苯地平可显着增加循环 EPCs，改善 BM-EPCs 功能，促进血管生成，并减少糖尿病小鼠的脑缺血损伤。此外，我们发现低剂量硝苯地平显着增加内皮一氧化氮合酶 (eNOS) 表达和细胞内 NO 水平，并降低细胞内 O _2水平^。−和糖尿病小鼠 BM-EPC 中的血小板反应蛋白-1/2（TSP-1/2，一种有效的血管生成抑制剂）。在培养的 BM-EPC 中，硝苯地平 (0.1, 1 μM) 的共同处理呈剂量依赖性地防止高葡萄糖诱导的迁移损伤，并抑制高葡萄糖诱导的 TSP-1 分泌和超氧化物过量产生。在大脑中动脉闭塞的小鼠中，静脉注射硝苯地平治疗的糖尿病 BM-EPCs 与注射用载体治疗的糖尿病 BM-EPCs 和供体来源的 BM-EPCs 相比，显示出更大的促进局部血管生成和减少脑缺血损伤的能力。 EPCs 归巢于受体缺血的大脑。总之，低剂量硝苯地平可以增强内皮祖细胞的血管生成潜能，防止糖尿病小鼠发生脑缺血损伤。