Astragaloside IV improves angiogenesis under hypoxic conditions by enhancing hypoxia-inducible factor-1α SUMOylation

Abstract

Improving angiogenic capacity under hypoxic condi- tions is essential for improving the survival of skin grafts, as they often lack the necessary blood supply. The stable expres- sion levels of hypoxia-inducible factor-1α (HIF-1α) in the nucleus directly affect the downstream vascular endothelial growth factor (VEGF) signaling pathway and regulate angio- genesis in a hypoxic environment. Astragaloside IV (AS-IV), an active component isolated from Astragalus membranaceus, has multiple biological effects including antioxidant and anti-diabetic effects, and the ability to provide protection from cardiovascular damage. However, the mechanisms underlying these effects have not previously been elucidated. The present study investigated whether AS-IV promotes angiogenesis via affecting the balance between ubiquitination and small ubiquitin-related modifier (SUMO) modification of HIF-1α. The results demonstrated that persistent hypoxia induces changes in expression levels of HIF-1α protein and significantly increases the proportion of dysplastic blood vessels. Further western blotting experiments showed that rapid attenuation and delayed compensation of SUMO1 activity is one of the reasons for the initial increase then decrease in HIF-1α levels. SUMO1 overexpression stabilized the presence of HIF-1α in the nucleus and decreased the extent of abnormal blood vessel morphology observed following hypoxia. AS-IV induces vascular endo- thelial cells to continuously produce SUMO1, stabilizes the HIF-1α/VEGF pathway and improves angiogenesis in hypoxic conditions. In summary, the present study confirmed that AS-IV stimulates vascular endothelial cells to continuously resupply SUMO1, stabilizes the presence of HIF-1α protein and improves angiogenesis in adverse hypoxic conditions, which may improve the success rate of flap graft surgery following trauma or burn.