Low-dose nifedipine rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice

Cheng Peng1,2, Li-jun Yang1, Chuan Zhang3, Yu Jiang4, Liu-wen-xin Shang4, Jia-bei He1, Zhen-wei Zhou1, Xia Tao4, Lu Tie5, Alex F. Chen2, He-hui Xie1,2
1 School of Public Health and Hongqiao International Institute of Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
2 Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
3 School of Medicine, Shanghai University, Shanghai 200444, China
4 Department of Pharmacy, Second Affiliated Hospital of Naval Medical University, Shanghai 200003, China
5 Department of Pharmacology, School of Basic Medical Sciences, Peking University and Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing 100191, China
Correspondence to: Lu Tie:, Alex F. Chen:, He-hui Xie:,
DOI: 10.1038/s41401-022-00948-w
Received: 6 December 2021
Accepted: 24 June 2022
Advance online: 1 January 1970


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 O .− and thrombospondin-1/2 (TSP-1/2, a potent 2 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.
Keywords: diabetes; nifedipine; endothelial progenitor cells; angiogenesis; cerebral ischemia; thrombospondins

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