Research Paper Volume 12, Issue 22 pp 22599—22613

miR-25-3p promotes endothelial cell angiogenesis in aging mice via TULA-2/SYK/VEGFR-2 downregulation

Chong Lian1,2,3, *, , Lei Zhao1,2,3, *, , Jiacong Qiu1,2,3, , Yang Wang1,2,3, , Rencong Chen1,2,3, , Zhen Liu1,2,3, , Jin Cui1,2,3, , Xiaonan Zhu4, , Xuejun Wen5, , Shenming Wang1,2,3, , Jinsong Wang1,2,3, ,

  • 1 Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
  • 2 National-Local Joint Engineering Laboratory of Vascular Disease Treatment, Guangzhou 510080, China
  • 3 Guangdong Engineering and Technology Center for Diagnosis and Treatment of Vascular Diseases, Guangzhou 510080, China
  • 4 Department of Pharmacology Laboratory, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
  • 5 Institute for Engineering and Medicine, Department of Biomedical Engineering, Chemical and Life Science Engineering, Virginia Commonwealth University, Richmond, VA 23284, USA
* Equal contribution

Received: April 27, 2020       Accepted: July 14, 2020       Published: November 17, 2020
How to Cite

Copyright: © 2020 Lian et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


In aging, the regulation of angiogenesis is a dynamic and complex process. We aimed to identify and characterize microRNAs that regulate angiogenesis during aging. We showed that, in response to vascular endothelial senescence, microRNA-25-3p (miR-25-3p) plays the role of an angiogenic microRNA by targeting TULA-2 (T-cell ubiquitin ligand-2)/SYK (spleen tyrosine kinase)/VEGFR-2 (vascular endothelial growth factor receptor 2) signaling in vitro and in vivo. Mechanistic studies demonstrated that miR-25-3p inhibits a TULA-2/SYK/VEGFR-2 signaling pathway in endothelial cells. In old endothelial cells (OECs), upregulation of miR-25-3p inhibited the expression of TULA-2, which caused downregulation of the interaction between TULA-2 and SYK and increased phosphorylation of SYK Y323. The increased SYK Y323 phosphorylation level upregulated the phosphorylation of VEGFR-2 Y1175, which plays a vital role in angiogenesis, while miR-25-3p downregulation in YECs showed opposite effects. Finally, a salvage study showed that miR-25-3p upregulation promoted capillary regeneration and hindlimb blood flow recovery in aging mice with hindlimb ischemia. These findings suggest that miR-25-3p acts as an agonist of TULA-2/SYK/VEGFR-2 and mediates the endothelial cell angiogenesis response, which shows that the miR-25-3p/TULA-2 pathway may be potential therapeutic targets for angiogenesis during aging.


MiR-25-3p: MicroRNA-25-3p; TULA-2: T-cell Ubiquitin Ligand-2; SYK: Spleen tyrosine kinase; VEGFR-2: Vascular Endothelial Growth Factor Receptor 2; OECs: Old Endothelial Cells; YECs: Young Endothelial Cells; EC: Endothelial Cell; MiRNA: MicroRNA; PTP: Protein Tyrosine Phosphatase; SYK Y323: the Y323 site of spleen tyrosine kinase; PI3K: Phosphatidylinositol 3-kinase; Co-IP: Co-immunoprecipitation; PVDF: Polyvinylidene fluoride; siRNA: small interfering RNA; GFR: Growth Factor Reduced; SEM: Standard Error of the Mean.