An ultrastructural study of macrovascular changes in rats with diabetes mellitus and hypertension

Numerous investigators have presented evidence of increased mortality in patients with diabetes mellitus due to cardiovascular disease. The reasons for a predisposition to vascular pathology that, in the advanced state, can lead to atherosclerosis are still unclear. Our hypotheses were: 1) the condition of diabetes mellitus in a streptozocin animal model may show vascular changes similar to early pathology in macrovessels, 2) since the model is normotensive, inducing hypertension will result in early atherogenic pathology, 3) the response to diabetic and/or hypertensive circumstances may be diversified due to the function of blood vessels, and 4) endothelium is the initiator of vascular pathology in diabetes. To test these hypotheses, we carried out a quantitative analysis of the renal and coronary arteries from rats using light, transmission and scanning electron microscopy. Diabetes mellitus was induced with streptozocin and hypertension was induced using deoxycorticosterone acetate. There were four experimental groups: control, control/hypertensive, diabetic, and diabetic/hypertensive. In the renal artery, the tunica media and luminal areas significantly increased in the hypertensive groups, but proportionately, the vessel dimensions did not alter, with all four groups having similar tunica media/lumen ratios. There was a significant elevation of extracellular matrix surrounding the smooth muscle cells of the tunica media in the renal artery due to the diabetic condition, although there were no changes in wall dimensions. Renal arteries from the control/hypertensive group had a significantly thickened tunica media as did the diabetic/hypertensive group over control values. The latter also had an even greater significant elevation of the extracellular matrix compared with either the diabetic or control/hypertensive group. This means that the composition of the tunica media had significantly altered, with more connective tissue. In addition, there was marked subendothelial invasion of macrophage-type cells and electrondense deposits of various shapes and densities. The number of adherent white blood cells, probably monocytes, on the endothelium was significantly increased in the renal artery from the hypertensive groups. In the coronary artery, in contrast, the pattern of pathological responses was different from that seen in the renal artery. The tunica media and luminal areas were significantly less in the diabetic condition even though there was no alteration in the makeup of the tunica media. The hypertensive groups had an altered composition of the tunica media with more extracellular matrix compared with the controls. Both control/hypertensive and diabetic/hypertensive groups had not only a significant increase in medial and luminal areas, but also both had a proportionately greater hypertrophy of the media compared with the increase in luminal areas. This resulted in significant differences in media/lumen ratios over normotensive controls. When the two hypertensive groups were compared with each other, the diabetic animals did not increase to the same extent as the nondiabetic did in both tunica media and luminal areas. In addition, in both hypertensive groups the adventitial area significantly increased over that in the respective controls, which was greater than the luminal hypertrophy, giving significant differences in adventitial to luminal ratios. The tunica intima did not show the striking early lesion stage seen in the renal arteries from the diabetic/hypertensive group, and none of the four groups had adherent white blood cells. We have, therefore, demonstrated different patterns of vascular changes due to the diabetic condition in this animal model. We have also shown that, with hypertension and diabetes combined, the early vascular pathology is exacerbated in the renal artery but not in the coronary artery. The vessel proportions in the coronary artery also changed due to hypertension, in contrast to the renal artery where vessels from animals in all four groups had similar wall/lumen ratios.Medicine, Faculty ofMedical Genetics, Department ofGraduat