Background: Geometrical alterations in the coronary resistance artery network and the potential involvement of Tenascin C (TNC) extracellular matrix protein were investigated in diabetic and control mice. Methods: Diabetes was induced by streptozotocin (STZ) injections (n = 7–11 animals in each group) in Tenascin C KO (TNC KO) mice and their Wild type (A/J) littermates. After 16–18 weeks the heart was removed and the whole subsurface network of the left coronary artery was prepared (down to branches of 40 \mum outer diameter), in situ pressure-perfused and studied using video-microscopy. Outer and inner diameters, wall thicknesses and bifurcation angles were measured on whole network pictures reconstructed into collages at 1.7 \mum pixel resolutions. Results: Diabetes induced abnormal morphological alterations including trifurcations, sharp bends of larger branches, and branches directed retrogradely (p 0.001 by the \chi{}^2 test). Networks of TNC KO mice tended to form early divisions producing parallelly running larger branches (p 0.001 by the \chi{}^2 probe). Networks of coronary resistance arteries were substantially more abundant in 100–180 \mum components, appearing in 2–5 mm flow distance from orifice in diabetes. This was accompanied by thickening of the wall of larger arterioles (>220 \mum) and thinning of the wall of smaller (100–140 \mum) arterioles (p 0.001). Blood flow should cover larger distances in diabetic networks, but interestingly STZ-induced diabetes did not generate further geometrical changes in TNC KO mice. Conclusions: Diabetes promotes hypertrophic and hypotrophic vascular remodeling and induces vasculogenesis at well defined, specific positions of the coronary vasculature. TNC plays a pivotal role in the formation of coronary network geometry, and TNC deletion causes parallel fragmentation preventing diabetes-induced abnormal vascular morphologies.