Occlusion of coronary vasa vasorum (VV) leads to hypoperfusion of the arterial vessel wall (AVW) possibly resulting in impaired solute transport. We hypothesize that high cholesterol (HC) facilitates development of atherogenesis in hypoperfused areas. Swine (40) underwent injection of gold‐coated μspheres (100μm) in left coronary artery. After the procedure 13 swine were studied immediately, 13 were fed a standard (C) and 14 a HC diet for 3 months prior to study. The LADs were harvested and snap‐frozen (cryo micro‐CT scanning). Hypoperfused areas in the AVW were defined by local reduction of CT‐values. The distance of μsphere to lumen (x) was measured, and foam/fat cells/mm 2 (f/fc) in hypoperfused and perfused areas were counted using histology. Linear relationship between x and hypoperfused AVW. In HC the f/fc # in media of hypoperfused areas is higher than in C (p=0.001). In HC f/fc # is higher in hypoperfused AVW areas compared to adjacent perfused areas (p<0.05). In C there is no difference in f/fc # between hypoperfused and perfused areas (p=0.92). In C and HC the f/fc # in intima of perfused, as well as in hypoperfused, areas is not different (p=0.9/0.5). Occlusion of VV leads to increased susceptibility of hypoperfused AVW areas for precursors of atherosclerosis with HC diet. The linear relationship of hypoperfused area to μsphere distance suggests that VV function as a plexus rather than a vascular tree. This study was supported by NIH grant HL065342.