Abstract
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.
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Acknowledgements
This work was supported by grants from the Ministry of Science and Technology of China (2021YFA0804803), the National Natural Science Foundation of China (81870189, 82070266, 81900243, 81930012, 81730013, 92168120 and 81974506), and the Beijing Natural Science Foundation (Z200019).
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HHX conceived and designed the experiments. CP, LJY, YJ, LWXS, JBH and ZWZ performed the experiments. HHX, LT, CZ and AFC analyzed and interpreted the data. XT provided intellectual contribution and useful discussion. HHX and CP wrote the manuscript.
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Peng, C., Yang, Lj., Zhang, C. et al. Low-dose nifedipine rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice. Acta Pharmacol Sin 44, 44–57 (2023). https://doi.org/10.1038/s41401-022-00948-w
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DOI: https://doi.org/10.1038/s41401-022-00948-w
