PROJECT SUMMARY Diabetes is a heterogeneous disease characterized by chronic poor glycemic control, resulting in pathological changes in tissues throughout the body. Chronic hyperglycemia causes the cardiovascular system to undergo growth and remodeling (G&R) that is captured hypertension and increased arterial stiffness, both significant risk factors for cardiovascular disease. Diabetes results in both cellular and matrix changes in arterial health, and then each of these components further drive the pathological G&R by responding to the direct effects of the disease. Fortunately, there exist medical and lifestyle interventions to help mitigate the diabetic disease state and restore glycemic control. Large elastic arteries like the aorta serve as capacitors to absorb changes in blood volume due to pulsatile pumping and protect the more fragile downstream microvasculature. Overall health and stiffness of these large vessels is captured in the clinic via pulse wave velocity which is elevated in diabetic patients, and there is evidence that the pulse wave velocity decreases back towards baseline following restoration of glycemic control. The overarching objective of this project is to determine how hyperglycemia affects aortic biomechanics and mechanobiology and whether restoration of normoglycemia is sufficient to reverse these changes. To establish how arterial biomechanics are affected by hyperglycemia, I first employed a diabetic mouse model to ascertain changes in active and passive wall mechanics, and these preliminary results demonstrate that chronic hyperglycemia results in stiffer and hypercontractile murine aortas. The central hypothesis of this proposal is that chronic hyperglycemia results in cellular and matrix aortic G&R, and glycemic recovery results in reversal of the cellular, but not matrix, phenotype, leading to partial rescue of aortic health. To test this hypothesis, I will utilize an inducible mouse model of chronic hyperglycemia that can subsequently be rescued by administration of Phloridzin. Experiments proposed in Aim 1 will determine the in vivo and ex vivo biomechanical changes in aortic health due to hyperglycemia and following treatment. Aim 2 will then explore how the tissue-scale mechanical changes arise by investigating how the matrix composition and cellular phenotype are affected by the disease and treatment. The experimental work of the first two Aims will be coupled with a multiscale, bio-chemo-mechanical computational model of aortic G&R in Aim 3. The computational model will provide mechanistic insight into the roles of cells and matrix in disease progression and possible regression, resolving information that is inextricable experimentally. Collectively, these data will elucidate aortic G&R due to chronic hyperglycemia, whether these changes can be reversed by restoration of glycemic control, and the mechanisms behind these processes. This proposed work will have broad implications in the conceptual understa...