Abstract: AIM:To observe vascular responsiveness to adiponectin in hypercholesterolemic rats and to investigate the mechanisms involved. METHODS: Fifty male Sprague Dawley (SD) rats were randomized to receive a regular rat chow diet or a high-fat diet for 0-16 weeks, and circulating cholesterol and adiponectin levels were determined. The aortas of rats were isolated and the expression of AMPK phosphoralytion (p-AMPK) and adiponectin receptor (AdipoR1) was detected. Aortas were incubated with recombinant full-length adiponectin (rAPN) and rAPN-induced AMPK phosphorylation was observed. rAPN was incubated with rat plasma for 4 h and then the effect of treated rAPN on AMPK phosphorylation in human umbilical vein endothelial cells was observed. RESULTS: Compared with that in rats fed with regular diet, cholesterol concentration increased after 8 weeks of the high-fat diet. Adiponectin levels in animals fed a high-fat diet significantly increased at 8 weeks and rapidly declined thereafter. The expression of rAPN-induced p-AMPK and AdipoR1 was reduced in rats fed a high-fat diet. Pre-incubation of rAPN with high-fat plasma rather than normal plasma significantly decreased the AMPK activation effect. CONCLUSION: The present study demonstrates that hypercholesterolemia causes vascular adiponectin resistance. Adiponectin modification/inactivation by unidentified factors in hypercholesterolemic plasma is likely responsible for early phase adiponectin resistance. A combination of adiponectin modification/inactivation reduced circulating adiponectin and decreased AdipoR1 expression and is responsible for late phase adiponectin resistance.