Vascular BK channels, composed of the pore-forming α-subunits (BK-α) and the regulatory β1 subunits (BK-β1) , is a key determinant of vasoreactivity, and its function is impaired in diabetes. However, our understanding of the mechanisms causing BK channel dysfunction in diabetic vessels is incomplete. The Sorbin and SH3 domain-containing protein 2 (Sorbs2) is abundantly expressed in vascular smooth muscle cells (SMCs) . We hypothesize that Sorbs2 is critical for vascular BK channel physiology. In this study, we compared vascular BK channel function between Sorbs2 KO and WT mice at 4 months of age. There was no difference in body weight and blood glucose between WT and Sorbs2 KO mice (body weight: 25.9±1.3 g of WT vs. 23.3±1.5 g of KO, n=14, p=N.S.; blood glucose: 166.4±7.7 mg/dL of WT vs. 152.2±12.2 mg/dL of KO, n=14, p=N.S.) . However, Sorbs2 KO mice have markedly reduced cell surface and cytoplasmic expression of BK-α and BK-β1, as well as BK channel-mediated vasodilation in carotid arteries with a maximal dilatation of 64.70±1.92% for WT mice (n=4) and 20.74±4.66% for KO mice (n=5, p<0.05) . Patch clamp experiments revealed that BK channel sensitivity to Ca2+ activation was impaired in the coronary SMCs of Sorbs2 KO mice (EC50: 2.87±0.68 µM, n=13, p<0.05) with decreased Hill coefficient (nH: 1.26) , compared to those of WT mice (EC50: 0.48±0.µM, nH: 2.70, n=13) . In vivo studies showed that Sorbs2 interacted with BK-α and BK-β1 protein in vascular SMCs. Silencing of Sorbs2 by shRNA decreased BK-α and BK-β1 expression, while adenoviral expression of Sorbs2 increased BK-α and BK-β1 expression in vascular SMCs. Most importantly, Sorbs2 expression was significantly reduced in the arteries of db/db type 2 diabetic mice and high fat diet-induced diabetic mice. Our results indicate that Sorbs2 plays an important role in regulating BK channel function and expression in vascular SMCs. Sorbs2 deficiency is a risk factor of BK channelopathy and vasculopathy in diabetes,independent of obesity and glucotoxicity.