SUMMARY:The alteration induced by diabetes on vascular permeability to serum albumin was investigated in the mesentery of streptozotocin-induced hyperglycemic rats. Double-tagged ( 125 I and dinitrophenol-haptenated) heterologous albumin was intravenously administered in normal and hyperglycemic animals, and the extravasation of the tracer was evaluated by radioactivity measurements and by morphometry at the ultrastructural level using quantitative protein A-colloidal gold immunocytochemistry. The results demonstrate that diabetes induces a significant increase in the permeability of the mesentery vessels to albumin. This increase is due to a more efficient transport of macromolecules by endothelial plasmalemmal vesicles and not to leakier interendothelial junctions. Passage across the endothelial basement membranes did not appear to be restricted in either the control or diabetic condition. However, in diabetes, the mesothelial basement membrane appeared to become modified and to restrain the passage of albumin toward the peritoneal cavity. After 3 months of diabetes, the rats presented a net increase in the average diameter of the blood vessels localized in the mesentery arcada (macrovascular hyperplasy) and a notable angiogenesis, manifested at the level of the microvasculature in the mesenteric windows. (Lab Invest 2000, 80:1171-1184.T he association of diabetes with vascular dysfunctions gradually evolving toward incapacitating or life-threatening vascular pathologies is undisputed. Extensive clinical observations and studies on animal models have amply documented that hyperglycemia accelerates and worsens atherosclerosis in large arteries (Colwell et al, 1988;Shantaram, 1999;Steiner 1997) and affects, although in different ways, the microvessels of selected vascular beds, such as those of the retina (Bazan et al, 1997;Cunha-Vaz, 1983;Porta, 1996;Ruggiero et al, 1997), kidney (Flyvbjerg, 1997;Mauer et al, 1984;Nyengaard and Bendtsen, 1993;Vlassara et al, 1994), and nerves (Cameron and Cotter, 1997;Malik et al, 1993; Tesfay et al, 1994). Particular attention has been directed to the study of diabetes-induced retinopathies and nephropathies, because of their obvious clinical implications. On the other hand, the impact of diabetes on other vascular beds has been generally overlooked. Therefore, it is not known whether diabetic microangiopathy concerns all blood vessels, creating a sort of "dysfunctional background" exacerbated in particular tissues by local factors to a full blown vascular pathology, or the vasculature of many organs is simply spared by the deleterious effects of hyperglycemia/ hypoinsulinemia. The latter hypothesis would fall in line with the ever-growing body of evidence pointing to important physiological and biochemical dissimilarities between various vascular segments (Boegehold, 1998;Rajotte et al, 1998;Thorin and Shreeve, 1998).Several morphologic features and physiologic parameters appear as leit motifs of diabetic microangiopathies. Among these, the thickening of the basement membran...