The role of salvianolic acid B and benzoylpaeoniflorin in enhancing angiogenesis through Nrf2/HO-1/VEGFA signaling axis in ischemic stroke recovery

Angiogenesis is one of the essential protective mechanisms that promote neural repair and regeneration after ischemic stroke (IS). Salvianolic Acid B (SAB) and Benzoyl paeoniflorin (BP) are compounds extracted from the Chinese medicines <i>Salvia miltiorrhiza</i> Bunge and <i>Paeonia suffruticosa</i> Andrews, respectively. We investigated whether SAB combined with BP alleviated IS by promoting micrangium angiogenesis and determined the potential molecular mechanisms. The impact of SAB-BP on angiogenesis after IS was investigated in middle cerebral artery occlusion (MCAO) rat model, ponatinib-induced ischemic stroke in zebrafish, and human umbilical vein endothelial cells (HUVECs). The neuroprotective effect of SAB-BP in rats was assessed using behavior tests and histopathological staining. The cerebral thrombosis assessment and angiogenesis assay were performed in the zebrafish model. Cell proliferation and angiogenesis in oxygen-glucose deprivation and reperfusion (OGD/R) HUVECs were assessed through cell viability, tube formation, migration, and invasion assays. Western blot analysis and immunofluorescence staining were used to determine the protein expression levels of Nrf2, HO-1, and VEGFA. The findings indicated that SAB-BP significantly reduced neurological impairment following IS and promoted the formation of functional vessels in the cerebral ischemic penumbra. Furthermore, SAB-BP up-regulated the protein expression of Nrf2, HO-1, HIF-1α, and VEGFA. Intriguingly, the pro-angiogenic effect of SAB-BP markedly restrained by adding the inhibitor of Nrf2 (ML385). Our study demonstrates that SAB-BP enhances angiogenesis following IS by modulating the Nrf2/HO-1/VEGFA signaling axis both <i>in vivo</i> and <i>in vitro</i>. SAB-BP could serve as a promising therapeutic agent for IS recovery.