Endothelial dysfunction, characterized by impairment of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) bioavailability, has been implicated in diabetic cardiovascular pathogenesis. In this study, low-molecular-weight fucoidan (LMWF), which has multiple biological activities including anti-inflammatory and anti-oxidative properties, was investigated for its protective effect against endothelial dysfunction in Goto-Kakizaki type 2 diabetic rats. LMWF (50, 100, or 200 mg/kg/day) or probucol (100 mg/kg/day) were given to diabetic rats for 12 weeks. Basal blood pressure, acetylcholine-or flow-mediated relaxation of mesenteric and paw arteries, endothelium-dependent dilation of aorta, eNOS phosphorylation, and NO production were measured using laser Doppler flowmetry, force myograph, hematoxylin and eosin staining, western blot analysis, and an NO assay. We found that LMWF robustly ameliorated the basal hypertension and impairment of endothelium-dependent relaxation in the aorta, as well as mesenteric and paw arteries in diabetic rats. In addition, the reduction in eNOS phosphorylation at Ser1177, eNOS expression, and NO production because of diabetes were partially reversed by LMWF treatment. However, probucol, a lipid-modifying drug with antioxidant properties, displayed only mild effects. Moreover, LMWF induced, in a dose-dependent manner, endotheliumdependent vasodilation and eNOS phosphorylation at Ser1177 in normal aorta, and also promoted Ser1177 phosphorylation and NO synthesis in primary cultured vasoendothelial cells. Thus, these data demonstrate for the first time that fucoidan protects vasoendothelial function and reduces basal blood pressure in type 2 diabetes rats via, at least in part, preservation of eNOS function. Fucoidan is therefore a potential candidate drug for protection of endothelium in diabetic cardiovascular complications. KEYWORDS: diabetes; endothelium-dependent vasodilation; endothelial nitric oxide synthase; low-molecular-weight fucoidan; nitric oxide Diabetic patients are at high risk of endothelial dysfunction and vascular lesions, because of multiple harmful stimuli, such as hyperglycemia, hyperlipidemia, and oxidative stress. These patients are susceptible to atherosclerosis, hypertension, and peripheral vascular disease. 1,2 It is well established that endothelium-derived nitric oxide (NO) maintains vascular homeostasis and health through vasodilation and protection of vasculature from various damaging agents. [3][4][5] Loss of NO induces increased activity of proinflammatory transcription factors, such as nuclear factor kappa B, resulting in expression of leukocyte adhesion molecules and production of chemokines and cytokines, which further promote endothelial inflammation and atherosclerosis. 5,6 Therefore, the endothelial dysfunction caused by imbalance of NO bioavailability in early-stage diabetes has been implicated as a sign or a predictor of a future cardiovascular event. [6][7][8] Mechanistically, a disturbance in endothelial NO synthase (eNOS) activity, refe...