Caffeic acid mitigates restenosis post-angioplasty via oxidative stress and inflammation reduction and mitochondrial protection in vascular smooth muscle cells

Angioplasty is the primary treatment for lower extremity arteriosclerosis obliterans, but the incidence of post-operative restenosis remains high. This condition is characterized by abnormal dedifferentiation of vascular smooth muscle cells (VSMCs), leading to neointimal formation. Caffeic acid (CA) is known for its antioxidant and anti-atherosclerotic properties. This study aims to investigate the effect of CA on neointimal formation after injury and its underlying mechanisms. In vitro experiments showed that CA (100 μM) significantly inhibited PDGF-induced proliferation, migration, and dedifferentiation of VSMCs, and reduced the excessive production of inflammatory factors and superoxide, while improving mitochondrial function. Pretreatment with the NF-κB inhibitor BAY11-7082 blocked the inhibitory effect of PDGF on VSMC phenotypic switching, suggesting that CA may exert its effects by regulating the NF-κB signaling pathway.To verify the in vivo effects of CA, we established a New Zealand rabbit iliac artery balloon injury model. The results showed that CA significantly reduced neointimal formation after balloon injury and inhibited the proliferation, migration, and dedifferentiation of VSMCs. This was confirmed by reversing the increase in osteopontin (OPN) and the decrease in α-smooth muscle actin (α-SMA) in the iliac artery. Furthermore, CA also inhibited oxidative stress and inflammatory responses. RNA sequencing revealed that CA inhibited the NF-κB signaling pathway, affecting the occurrence of in-stent restenosis (ISR).In summary, this study demonstrates that CA reduces neointimal formation after balloon injury and inhibits PDGF-induced VSMC dedifferentiation by inhibiting the NF-κB signaling pathway. These findings provide experimental evidence for CA as a potential anti-atherosclerotic therapeutic and preventive drug.