Background: Endothelial progenitor cells (EPCs) can alleviate atherosclerosis (AS) through their roles in endothelial repair and angiogenesis, but their function is often impaired under pathological conditions. Notoginsenoside R1 (NGR1), an extract from traditional Chinese medicine, has demonstrated therapeutic efficacy in alleviating AS. This study aims to investigate whether NGR1 ameliorates AS progression by restoring EPCs' dysfunction.

Methods: Apolipoprotein E-deficient (ApoE^-/-) mice were treated with angiotensin II for 4 weeks to establish an AS model, and treated with long-term infusion of NGR1 using an Alzet osmotic micropump. Metabolic characteristics and pathological changes in aortic tissues were measured using kits, Hematoxylin and Eosin (H&E) staining, Masson staining and Oil red O staining. EPCs extracted from mice were verified by immunofluorescence staining and then were treated with NGR1, Signal transducer and activator of transcription 3 (STAT3) overexpression plasmid (oe-STAT3) and / or Heparanase short hairpin RNA (shHPSE). The biological behaviors of EPCs were determined using cell counting kit 8, colony formation, scratch assay and tube formation assay. The relationship between STAT3 and HPSE was determined by Dual-luciferase reporter assay and Chromatin immunoprecipitation. The expression levels of STAT3, HPSE and syndecan-1 (SDC-1) were analyzed using Western blot and quantitative reverse transcription polymerase chain reaction (qRT-PCR) analyses.

Results: In vivo, NGR1 ameliorated disturbances of lipid metabolism and reduced aortic plaque formation in AS mice. In vitro, NGR1 facilitated the viability, proliferation, migration and tube formation of EPCs, while downregulating the expression levels of STAT3 and Heparanase and upregulating the SDC-1 expression level. However, these effects were reversed by oe-STAT3. STAT3 activated HPSE transcription, and the effects of oe-STAT3 on EPCs were reversed by shHPSE.

Conclusion: NGR1 restores EPCs' function by regulating the STAT3/HPSE axis, thereby alleviating the development of AS.