Neoagarotetraose from Marine Red Algae Attenuates Hypertensive Vascular Remodeling by Targeting FoxO4 to Inhibit Mitochondrial Superoxide Generation.

Oxidative stress is a key driver of hypertensive vascular remodeling. Neoagarotetraose (NA4), a marine-derived oligosaccharide, possesses potent antioxidant activity, but its effects on hypertension remain unexplored. Here, we investigated the role of NA4 in vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHR) and in SHR in vivo. NA4 treatment significantly reduced mitochondrial superoxide, H2O2 levels, and NADPH oxidase activity in SHR-VSMCs and suppressed their hyperproliferation and migration. RNA-seq identified FoxO4 as a significantly downregulated target. FoxO4 overexpression enhanced ROS production and VSMC dysfunction, and these effects were reversed by NA4. In SHR, oral administration of NA4 (200 or 250 mg/kg/day) for 4 weeks lowered blood pressure, attenuated vascular remodeling, and reduced arterial FoxO4 expression and superoxide generation. Collectively, NA4 ameliorates hypertensive vascular remodeling, and molecular docking suggests a potential interaction between NA4 and the FoxO4-ROS axis, highlighting its potential as a functional food ingredient for hypertension management.