Clinical and epidemiological evidence indicates that both genetic and environmental factors (independent of those governing susceptibility to develop diabetes) play important roles in the pathogenesis of large vessel disease associated with diabetes. Very little information is available, however, regarding the extent to which these factors modulate diabetic microangiopathy. Furthermore, virtually no studies have assessed and compared the impact of specialization of vascular structure and function (in different tissues) on the susceptibility to develop diabetic vascular complications. The research proprosed in this application will: 1) assess the influence of hereditary factors on degeneration of capillaries in eyes and kidneys of different strains of rats with chronic hyperglycemia, 2) determine whether the experimental mode of induction and age at the time of induction of diabetes are significant determinants of the expression of diabetic vascular disease, and 3) assess the influence of hypertension on the progression of diabetic microangiopathy. Capillary degenerative changes will be quantified in different vascular beds of the eye (retina, choriocapillaris, iris, ciliary body) and kidney of humans and rats in order to assess differences in susceptibility to injury by the diabetic milieu. Microvascular degenerative changes will be quantified by the use of electron microscopic and morphometric techniques and will be assessed three dimensionally in large capillary networks in unsectioned tissued by use of fluorescence microscopy. The latter technique provides unique views of entire capillary beds and will be used to assess pericyte degeneration, microaneurysms and capillary closure (basement membrane remnants of capillaries devoid of intact endothelial cells and pericytes). Electron microscopy will be used to quantify capillary size, endothelial cell dimensions, pericyte coverage of capillaries, necrosis of pericytes and endothelial cells, basement membrane thickening and capillary closure. The importance of this research is that it should permit a determination of which rat strain(s) is best suited for studies of the pathogenesis of diabetic microangiopathy and also provide additional insights into the importance of genetic versus environmental factors which might promote the initiation and/or progression of diabetic microvascular pathology.
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