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 Lian^1,^2,³, Lei Zhao^1,^2,³, Jiacong Qiu^1,^2,³, Yang Wang^1,^2,³, Rencong Chen^1,^2,³, Zhen Liu^1,^2,³, Jin Cui^1,^2,³, Xiaonan Zhu⁴, Xuejun Wen⁵, Shenming Wang^1,^2,³, Jinsong Wang^1,^2,³

¹Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
²National-Local Joint Engineering Laboratory of Vascular Disease Treatment, Guangzhou 510080, China
³Guangdong Engineering and Technology Center for Diagnosis and Treatment of Vascular Diseases, Guangzhou 510080, China
⁴Department of Pharmacology Laboratory, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
⁵Institute 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, 2020Accepted: July 14, 2020Published: November 17, 2020

https://doi.org/10.18632/aging.103834

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.

Abstract

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.