Hemodynamic Systems Analysis of Capillary Network Remodeling During the Progression of Type 2 Diabetes

P>Objective: Early alterations in the skeletal muscle microvasculature may contribute to the onset and progression of type 2 diabetes (DM2) by limiting insulin and glucose availability to skeletal muscle. Microvascular alterations reported with DM2 are numerous and include impaired endothelium-mediated vasodilation, increased arteriole wall stiffness, and decreased capillary density. Most previous analyses of skeletal muscle microvascular architecture have been limited to skeletal muscle cross sections and thus have not presented an integrated, quantitative analysis of the relative significance of observed alterations to elevated microvascular network resistance and decreased blood flow. In this work, we tested the hypothesis that the onset of diabetes would influence microvascular architecture in a manner that would significantly increase capillary network resistance and reduce blood flow. Methods and Results: In whole-mount spinotrapezius muscle capillary networks from Zucker diabetic fatty (ZDF) rats before and after the onset of DM2, we found a significant 37% decrease in microvascular branching and a 19% decrease in microvessel length density associated with the onset of the disease. This was previously indiscernible in skeletal muscle cross-section data. Hemodynamic computational analysis revealed that the changes in DM2 capillary network connectivity result in a significant 44% decrease in computed capillary network flow compared to controls. A hemodynamic sensitivity analysis showed that DM2 networks were predicted to be less robust in their ability to maintain perfused network surface area in the event of upstream terminal arteriole constriction. Conclusions: This study illustrates that capillary network connectivity is altered by DM2 and this negatively impacts microvascular hemodynamics. This work can serve as a basis for a more quantitative approach to evaluating DM2 microvascular networks and their potential use as an early diagnostic aid and/or method for identifying therapeutic targets.