Alterations in coronary resistance artery network geometry in diabetes and the role of Tenascin C

Abstract

Funding Acknowledgements Type of funding sources: None. Background and Aims: Geometrical alterations in the coronary resistance artery network and potential involvement of the Tenascin C (TNC) protein were examined in diabetic mice. Methods Diabetes was induced by streptozotocin injections (n=7-11 animals in each group) in Wild type (A/J) and Tenascin C KO (TNC KO) mice, and 16-18 weeks later the heart was removed and the whole subsurface network of the left coronary artery was microprepared (down to branches of 40 µm 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 µm pixel resolutions. Results Diabetic networks featured abnormal morphological alterations including trifurcations, sharp bends of larger branches, and branches directed in the retrograde direction (p<0.001 by the χ2 test). Networks of TNC KO mice tended to form early divisions producing parallel running larger branches (p<0.001 by the χ2 probe). Diabetic networks were substantially more abundant in 100-180 µm components, appearing in 2-5 mm flow distance from orifice. This was accompanied by thickening of the wall of larger arterioles (>220 µm) and thinning of the wall of a population of smaller (100-140 µm) arterioles (p<0.001). Interestingly, diabetes model by STZ-injection did not induce further geometrical changes in TNC KO mice. Blood flow should cover larger distances in diabetic networks. Conclusion In diabetic mice, a combined network remodelling of the coronary vasculature was observed with hypertrophic and hypotrophic remodelling and vasculogenesis at well defined, specific positions of the network. TNC plays an important role in the formation of network geometry, and TNC knockout induces parallel fragmentation preventing diabetes-induced abnormal vascular morphologies