Salvianolic acid A promotes angiogenesis after stroke by targeting AKT to alleviate oxidative stress.

Ischemic stroke (IS) remains a devastating cerebrovascular disease associated with high morbidity, mortality, and disability, while effective restorative therapies remain limited, highlighting an urgent unmet clinical need. Post-stroke angiogenesis contributes to vascular remodeling, restoration of cerebral blood flow, and neurovascular regeneration, making it a promising therapeutic target for IS repair. Salvianolic acid A (SAA), a phenolic acid from Salvia miltiorrhiza (Danshen), protects vascular endothelial cells and enhances neurogenesis, but its role and mechanisms in post-stroke angiogenesis remain unclear. This study investigated the effects and molecular mechanisms of SAA on post-stroke angiogenesis in vitro and in vivo. In vivo, an autologous thrombus-induced rat stroke model was established by electrocoagulation to evaluate the effects of SAA on neurological recovery and angiogenesis. In vitro, hydrogen peroxide (H₂O₂)-induced oxidative damage in human brain microvascular endothelial cells (HBMECs) was used to investigate the protective effects of SAA on endothelial function. Network pharmacology, molecular docking, and surface plasmon resonance (SPR) identified targets, with mechanistic verification both in vitro and in vivo. In the rat stroke model, SAA improved neurological deficits and enhanced functional recovery in a dose- and time-dependent manner. It also increased peri-infarct microvessel density, promoted vascular maturation, and upregulated pro-angiogenic factors (VEGF-A, Ang-1) and tight junction proteins (TJPs) (ZO-1, Occludin, Claudin-5). In HBMECs, SAA alleviated oxidative stress, enhanced proliferation, migration, and tube formation. Network pharmacology and SPR confirmed AKT as a core target of SAA, further activating the Nrf2 signaling pathway. AKT inhibitor MK-2206 counteracted the pro-angiogenic effect of SAA. In conclusion, SAA promotes post-stroke angiogenesis by targeting AKT and activating Nrf2-mediated antioxidant signaling, thereby protecting vascular endothelial function and improving neurological recovery. These findings provide new insights into vascular repair after IS and highlight SAA as a potential therapeutic candidate for stroke recovery via modulating angiogenesis.