ABSTRACT Neointima formation, characterized by similarities to tumor‐like growth, plays a pivotal role in the progression of vascular occlusive diseases. Oroxylin A (OroA), a bioactive flavonoid from Scutellaria roots, shows protective effects against cardiovascular diseases and cancers. This study explores whether OroA inhibits neointima formation caused by vascular injury and investigates the mechanisms involved. Models of carotid artery ligation and guide wire‐induced injury were used to study vascular smooth muscle cell (VSMC) phenotypic switching and neointima formation. Glycolytic activity and oxidative phosphorylation were evaluated using extracellular acidification rates and oxygen consumption rates, respectively. Western blot and quantitative real‐time PCR were utilized to measure the expression of contractile and proliferative markers, glycolytic enzymes, and intracellular signaling pathways. For rescue experiments, an adenovirus encapsulated in pluronic gel was used to overexpress HIF‐1α in injured vascular tissue. OroA effectively inhibited VSMC phenotypic switching and neointima formation by suppressing vascular injury‐induced glycolytic reprogramming. Mechanistically, the vascular injury‐induced upregulation of mammalian target of rapamycin complex 1 (mTORC1)–hypoxia‐inducible factor‐1α (HIF‐1α) signaling increases the aerobic glycolysis of VSMCs. OroA attenuated mTORC1–HIF‐1α signaling‐mediated aerobic glycolysis by preventing the phosphorylation of tuberous sclerosis complex 2 (TSC2) at serine 939. Notably, the overexpression of HIF‐1α reversed the inhibitory effects of OroA on VSMC phenotypic switching and neointima formation. This study suggests that OroA mitigates neointima formation by inhibiting the TSC2/mTORC1/HIF‐1α‐dependent glycolysis pathway, indicating its potential as a therapeutic agent for vascular occlusive diseases.
Cao et al. (Sun,) studied this question.