CXCR7 Agonist TC14012 Improves Angiogenic Function of Endothelial Progenitor Cells via Activating Akt/eNOS Pathway and Promotes Ischemic Angiogenesis in Diabetic Limb Ischemia.

Abstract

PURPOSE:

Endothelial progenitor cells (EPCs) play a critical role in repairing damaged vessels and triggering ischemic angiogenesis, but their number is reduced and function is impaired under diabetic conditions. Improving EPC function has been considered a promising strategy to ameliorate diabetic vascular complications. In the present study, we aim to investigate whether and how CXCR7 agonist TC14012 promotes the angiogenic function of diabetic EPCs.

METHODS:

High glucose (HG) treatment was used to mimic the hyperglycemia in diabetes. Tube formation, cell scratch recovery and transwell assay, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, and cleaved-caspase3 expression were used to evaluate the angiogenic capability, cell migration, and apoptosis of EPCs, respectively. Hind limb ischemia (HLI) model was used to appraise the ability of TC14012 in promoting diabetic ischemic angiogenesis in vivo.

RESULTS:

HG treatment impaired EPC tube formation and migration, and induced EPC apoptosis and oxidative damage, while TC14012 rescued tube formation and migration, and prevented HG-induced apoptosis and oxidative damage of EPCs. Furthermore, these beneficial effects of TC14012 on EPCs were attenuated by specific siRNAs against CXCR7, validating that CXCR7 is a functional target of TC14012 in EPCs. Mechanistic studies demonstrated that HG treatment reduced CXCR7 expression in EPCs, and impaired Akt and endothelial nitric oxide synthase (eNOS) phosphorylation and nitric oxide (NO) production; similarly, these signal impairments in HG-exposed EPCs could be rescued by TC14012. However, the protective effects of TC14012 on tube formation and migration, Akt and eNOS phosphorylation, and NO production in HG-treated EPCs were almost completely abolished by siRNAs against CXCR7 or Akt specific inhibitor wortmannin. More importantly, in vivo study showed that TC14012 administration enhanced blood perfusion recovery and angiogenesis in the ischemic hind limb and increased the EPC number in peripheral circulation of db/db mice, demonstrating the capability of TC14012 in promoting EPC mobilization and ischemia angiogenic function.

CONCLUSION:

TC14012 can prevent EPCs from HG-induced dysfunction and apoptosis, improve eNOS activity and NO production via CXCR7/Akt signal pathway, and promote EPC mobilization and diabetic ischemia angiogenesis.

• Authors: Kai Wang, Shiyue Sun, Guigui Zhang, Zixian Lu, Hui Chen, Xia Fan, Chunjie Gu, Xiaohong Pan, Qian Lin, Oscar Chen, Lu Cai, Xiaozhen Dai, Xiao Wang, Chaosheng Lu, Xiaoqing Yan, Yi Tan
• Journal: Cardiovascular drugs and therapy (Cardiovasc Drugs Ther) Vol. 37 Issue 5 Pg. 849-863 (10 2023) ISSN: 1573-7241 [Electronic] United States
• PMID: 35471717 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Chemical References

• Proto-Oncogene Proteins c-akt
• TC14012
• Nitric Oxide Synthase Type III

Topics

• Mice
• Animals
• Endothelial Progenitor Cells (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Nitric Oxide Synthase Type III (metabolism)
• Diabetes Mellitus
• Ischemia (drug therapy, complications, metabolism)
• Signal Transduction
• Cell Movement
• Neovascularization, Physiologic