Striatin is a scaffolding protein that plays a role in vesicular trafficking in neurons. Striatin binds to regulatory proteins such as caveolin-1, Ca2+-calmodulin, Gαi and phosphatase 2A, thereby activating transduction molecules such as eNOS and mitogen-activated protein kinase. We have shown that striatin colocalizes with the minerlacorticoid receptor (MR), and that MR activation increases striatin levels in vascular cells in vivo and in vitro. To test the hypothesis that striatin is a critical regulator of vascular function, WT mice and heterozygous striatin-deficient mice lacking one allele for striatin (Strn-HET) were randomized in a crossover intervention to liberal salt (HS, 1.6% NaCl) and low salt (LS, 0.03% NaCl) diets for 7 days on each diet. Blood pressure (BP) and plasma aldosterone (ALDO) levels were measured and the aorta was excised to assess vascular function. Δ Systolic BP (BP on HS - BP on LS) was in Strn-HET > WT (16.5±3.5 vs 3.7±6.1 mmHg). Plasma ALDO levels were higher during LS diet, but were similar in WT and Strn-HET mice (152.6±23.9 vs 131.5±47.6 ng/dL on LS; 72.9±7.7 vs 70.9±8.3 ng/dL on HS). Phenylephrine (Phe) caused vascular contraction that was in Strn-HET (max 0.31±0.07g) > WT (0.23±0.07g). Also, high KCl (96 mM)-induced contraction was in Strn-HET (0.44±0.06g) > WT mice (0.33±0.05g) on HS diet, suggesting that the enhanced vascular contraction is not limited to a particular receptor. Endothelium removal, NOS inhibitor L-NAME and guanylate cyclase inhibitor ODQ enhanced contraction and increased sensitivity to Phe in WT mice and to a greater extent in Strn-HET mice on HS but not LS diet. On HS, acetylcholine (ACh) relaxation was in Strn-HET (max 33.16±4.47%) < WT (50.94±10.88%). ACh relaxation was blocked by endothelium removal, L-NAME and ODQ, supporting a role of the NO-cGMP pathway. Vascular relaxation to the exogenous NO donor sodium nitroprusside was not different between groups. Thus striatin deficiency during HS diet is associated with salt sensitivity of BP, enhanced vasoconstriction and decreased vascular relaxation. The results suggest a critical role for striatin, possibly through modulation of endothelium-dependent NO-cGMP pathway, in regulation of vascular function and BP during changes in dietary sodium intake.