Abstract
Vascular endothelial dysfunction constitutes a pivotal initiating event in atherosclerosis (AS) pathogenesis, characterized by upregulated inflammatory factors, elevated reactive oxygen species (ROS) production, and excessive nitric oxide (NO) depletion. The exogenous delivery of NO, while minimizing adverse effects on the human body, presents a potent strategy for maintaining vascular homeostasis during pathological events. Herein, a natural ultrasound (US)-triggered and "on-demand" NO booster (FPG) is constructed using S-nitrosoglutathione (GSNO) as the NO donor and fucoidan for its anti-inflammatory and antioxidant properties. RNA sequencing and western blot analyses reveal that US-activated FPG modulates nuclear factor erythroid-2-related factor 2 (Nrf2), nuclear factor kappa-B (NF-κB), and vascular endothelial growth factor (VEGF)/endothelial NO synthase (eNOS) pathways in oxidized low-density lipoprotein (ox-LDL)-stimulated human umbilical vein endothelial cells (HUVECs). This modulation attenuates oxidative stress, suppresses inflammatory responses, and enhances angiogenesis. Furthermore, US and histopathological imaging examinations indicate that combined FPG-US therapy reduces plaque area (% plaque area/tissue area: 0.10 ± 0.04%; P = 0.003 vs. high-fat diet group (2.25 ± 0.10%)) and preserves vascular integrity in high-fat diet mice. Collectively, this natural US-responsive NO booster establishes a robust foundation for developing targeted therapies against endothelial dysfunction and advancing innovative pharmacotherapeutic strategies for cardiovascular diseases.