Salvia miltiorrhiza augments endothelial cell function for ischemic hindlimb recovery

Abstract Salvia miltiorrhiza ( Salvia miltiorrhiza ) root , as a traditional herb , is widely applied to pharmacotherapy for vascular system disease. In this study, we elucidate the therapy mechanism of Salvia miltiorrhiza by using a model of hindlimb ischemia. Blood perfusion measurement showed that intravenous administration of the Water Extract of Salvia miltiorrhiza (WES) could facilitate damaged hindlimb blood flow recovery and blood vessel regeneration. In vitro mRNA screen assay in cultured human umbilical vein endothelial cells (HUVECs) show that WES induced increased NOS3 , VEGFA, and PLAU mRNA levels. Endothelial NOS (eNOS) promotor reporter analysis revealed that WES and the major ingredients danshensu (DSS) could enhance eNOS promoter activity. Additionally, we found that WES and its ingredients, including DSS, protocatechuic aldehyde (PAI), and salvianolic acid A (SaA), promoted HUVECs growth by the endothelial cell viability assays. A mechanistic approach confirmed that WES augments HUVECs proliferation through the activation of extracellular signal-regulated kinase (ERK) signal pathway. This study reveals that WES promotes ischemic remodeling and angiogenesis through its multiple principal ingredients, which target and regulate multiple sites of the network of the blood vessel endothelial cell regenerating process.