Nitric oxide (NO) depletion induces hypertension, oxidative stress and arterial stiffness. Previous study has shown that tetrahydrocurcumin (THU), a major antioxidant and anti-inflammatory agent, improved aortic stiffening of rats with NO-deficiency, however, the associated mechanism remains unclear. The objective of this study was to determine whether THU could attenuate vascular dysfunction and aortic remodeling in NO-deficient rats. The procedures and experimental protocols were reviewed and approved by the Institutional Animal Ethics Committee of Khon Kaen University, Thailand. Male Sprague-Dawley rats weighing 200-220 g were divided into normotensive and hypertensive groups (n=6-8/group). Hypertension was induced by administering Nω-nitro-L-arginine methyl ester (L-NAME) at a dose of 50 mg/kg/day in their drinking water for 5 weeks. After 3 weeks, hypertension had been established and was sustained in all animals. During the last two weeks, L-NAME hypertensive rats were randomly divided into three treatment groups. Group 1 was intragastrically administered with polyethylene glycol (PG), a vehicle. Group 2 and 3 were intragastrically administered with THC for 2 weeks at doses of 50 and 100 mg/kg/day, respectively. The normotensive controls were received tap water ad libitum and intragastrically administered with PG. At the end of treatment, animals were anesthetized with pentobarbital sodium (60 mg/kg body weight, i.p.), arterial blood pressure and vascular response to acetylcholine (3, 10 and 30 nmol/kg, i.v.) were determined. Thereafter, rats were sacrificed by overdose of an anesthetic drug. The thoracic aortas were excised and used for quantitative morphometric analysis of structural changes and immunohistochemistry staining of MMP-2. Values are means ± S.E.M., compared by one way ANOVA. L-NAME significantly increased blood pressure, blunted vascular response and induced aortic remodeling. THU 50 and 100 mg/kg/day significantly decreased mean arterial pressure (174 ± 2 and 165 ± 2 mmHg, respectively vs. 189 ± 2 mmHg in L-NAME control rats; P < 0.01), and prevented the reduction in endothelium-dependent vasodilatation. THU reduced the increases in media thickness, cross-sectional area, smooth muscle cells proliferation and collagen accumulation in the aortic wall. Increased MMP-2 expression was found in the aortas of L-NAME, and THU at test doses significantly reduced it (P < 0.05). Our results suggest that MMP-2 plays a role in L-NAME hypertension and its structural and functional vascular changes, which were attenuated by THU.