Ferulic Acid in Combination with Astragaloside IV Promotes Angiogenesis in a High-Glucose Environment via Activating the HIF-1 Signaling Pathway

Abstract

Background: The healing process in diabetic wounds is an emerging challenge, emphasizing the development of new pharmacologic strategies. Ferulic acid (FA) and astragaloside IV (AS-IV) have been recognized for their angiogenic potential, but how their combination impacts the angiogenesis under a high-glucose environment is yet to be explored. Therefore, this study was designed to assess the synergistic effects of FA and AS-IV and their underlying mechanisms on angiogenesis in a high-glucose environment. Methods: Network pharmacology was utilized to screen the common targets associated with diabetic wounds, as well as FA and AS-IV. Subsequently, the signal pathways involved in these common targets were enriched using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Furthermore, the angiogenesis-promoting effects of FA and AS-IV were validated using flow cytometry, scratch assay, and tube formation assay. Additionally, the molecular mechanism underlying the impacts of FA and AS-IV on angiogenesis was evaluated using si-RNA interference assay. Results: Using bioinformatics analysis, 101 common target genes linked to diseases were identified. These target genes were enriched in various signaling pathways such as hydroxylated hypoxia-inducible factor 1 (HIF-1) signaling pathway and vascular endothelial growth factors (VEGFs) signaling pathway. Furthermore, cytological experiments revealed that FA and AS-IV promoted angiogenesis under a high-glucose condition by activating the HIF-1 signaling pathway. The combination of these two drugs significantly reduced the apoptosis level, increased cell migration, and promoted tube formation. Additionally, they increased the expression levels of VEGFs, vascular endothelial growth factor receptor 2 (VEGFR2), and HIF-1α proteins. Conversely, the protein expression level of the von Hippel-Lindau tumor-suppressor protein (VHL) significantly decreased. These effects were partially reversed when HIF-1α was down-regulated using specific si-HIF-1α. Conclusions: FA in combination with AS-IV promotes angiogenesis within a high-glucose environment by activating the HIF-1 signaling pathway. Hence, FA+AS-IV might be a promising option for treating diabetic wounds. These findings provide a novel experimental and theoretical basis for managing diabetic wounds.