LncRNA GUSBP5-AS promotes EPC migration and angiogenesis and deep vein thrombosis resolution by regulating FGF2 and MMP2/9 through the miR-223-3p/FOXO1/Akt pathway.

Li-Li Sun,Xiao-Long Du,Lun Xiao,Xu-Dong Jiang,Wen-Dong Li,Feng-Rui Lei,Xiao-Qiang Li

doi:10.18632/aging.102904

Abstract

Long non-coding RNAs (lncRNAs) play an essential role in multitudinous physiological and pathological processes, including vascular disease. We previously showed that lncRNA GUSBP5-AS (enst00000511042) is upregulated in endothelial progenitor cells (EPCs) of deep veni thrombosis (DVT) patients. Here, we investigate the role and mechanism of GUSBP5-AS in EPCs and DVT. Using the DVT model, we found that GUSBP5-AS significantly reduced the thrombus size and weight and enhanced the homing ability of EPC to DVT sites to promote resolution and recanalization of thrombus. GUSBP5-AS promoted cell cycle progression, proliferation, migration and invasion in EPCs, enhanced EPC angiogenesis in vitro and in vivo, and inhibited apoptosis. Strikingly, this study showed that GUSBP5-AS was unbalanced and modulated Forkhead Box Protein O1 (FOXO1) in EPCs in patients with DVT by interacting with miR-223-3p. Mechanistically, GUSBP5-AS functions as a sponge of miR-223-3p, which targets FOXO1. Both GUSBP5-AS knockdown and miR-223-3p overexpression remarkably inhibited angiogenesis, migration and invasion in EPCs. Additionally, our data suggested that GUSBP-AS activated the Akt pathway and enhanced fibroblast growth factor 2 (FGF2), matrix metalloproteinase-2/9 (MMP2/9) and F-actin expression. Taken together, this study indicates that GUSBP5-AS modulates angiogenesis, proliferation and homing ability of EPCs via regulating FGF2 and MMP2/9 expression through the miR-223-3p/FOXO1/Akt pathway, which may provide a new direction for the development of DVT therapeutics.

Highlights

Deep vein thrombosis (DVT) is a blood clot that forms within a deep vein, especially in leg veins such as the femoral vein
We found that GUSBP5-AS promotes angiogenesis and cell proliferation, migration, and invasion, and inhibits apoptosis in endothelial progenitor cells (EPCs) by modulating fibroblast growth factor 2 (FGF2) and matrix metalloproteinase-2/9 (MMP2/9) expression through the miR-223-3p/FOXO1 (Forkhead Box Protein O1)/Akt pathway
We investigated whether GUSBP5-AS regulates the homing ability of EPCs to thrombotic sites and participates in DVT recanalization and resolution

Summary

Introduction

Deep vein thrombosis (DVT) is a blood clot that forms within a deep vein, especially in leg veins such as the femoral vein. DVT can be potentially life-threatening when a blood clot breaks off and develops into pulmonary embolism (PE), leading to sudden cardiovascular collapse and death [4, 5]. DVT and PE form a single disease process named venous thromboembolism (VTE), which is the third most common vascular disease in the United States [6, 7]. The quality of life of patients with DVT is severely affected, especially when PTS is present [5, 9]. It is important and necessary to study the molecular mechanism of DVT and to explore alternative therapies

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Results

Conclusion