Obesity and diabetes are associated with structural remodeling and hypercontractility of small arteries. The degree and type of remodeling depends on the vascular bed and severity of the obese/diabetic state. In this study, remodeling was investigated using pressure myography of small pial arteries (PA) and terminal mesenteric arteries (TMA) from male castrated Göttingen minipigs (79.5 ± 0.3 weeks; N=21) after high-fat feeding (HFD; N=7), HFD with streptozotocin-induced diabetes (HFD/STZ; N=7), or chow feeding (lean control; LC; N=7). In vivo plasma parameters (implanted IV-catheter; anaesthesia w. tiletamin and zolazepam i.m., both 0.81 mg/kg) included total cholesterol (TC), triglyceride (TG), glucose (GLU), fructosamine (FRA), and insulin (INS). We quantitated, by Q-PCR, vessel expression levels of putative structural remodeling genes (ROCK1; MMP2; TIMP1; TGM2), and several Ca2+ (Cacna1C/G/H, TRPV4) and K+ channel genes (Kcnj2, Kcnn3, Kcnn4) involved in tone regulation. Using linear regression analysis, we correlated structural parameters, plasma parameters, and gene expression levels. Hypotheses: 1) Remodeling in HFD and HFD/STZ is correlated with distinct changes in plasma parameters and gene expression. 2) Hyperglycemia leads to altered ion channel expression, which potentially is involved in contractility changes. In TMAs from HFD/STZ pigs the passive lumen diameter (PLD) and wall cross-sectional area (CSA) were increased vs. LC, with little or no change in wall:lumen ratio and elastic modulus. In TMAs from HFD pigs, PLD was in-between that observed in LC and HFD/STZ, and CSA was not different from that observed in HFD/STZ. We observed qualitatively similar, albeit non-significant, structural changes in PA from HFD and HFD/STZ vs. LC. HFD pigs had increased BW, % body fat, TC, TG, and INS. HFD/STZ pigs had increased TC, TG, FRA, and GLU. As BW was not correlated with PLD, outward remodeling was not an effect of body size. Two genes (Cacna1G, MMP2) were down-regulated in HFD vs. LC. Ca2+ channels (Cacna1C, Cacna1G, Cacna1H), K+ channels (Kcnj2, Kcnn3, Kcnn4), and remodeling genes (Rock1, MMP2, and TGM2) were upregulated in HFD/STZ vs. LC or HFD. Structural parameters (PLD, CSA) were positively correlated with plasma lipids (TC, TG), and with ROCK1 and TGM2 expression. ROCK1 and TGM2 expression was positively correlated with GLU and FRA. In general, ion channel expression was positively correlated with GLU and FRA, and negatively correlated with INS. Obesity with diabetes causes outward hypertrophic remodeling of small arteries in Göttingen minipigs. Remodeling is positively correlated with plasma lipid levels and expression of ROCK1 and TGM2 genes, which are upregulated in hyperglycemia. Outward structural remodeling in small arteries is driven by several factors present in obesity/diabetes, and this translational model allows for investigation of the molecular mechanisms involved.