Cerebrovascular remodeling and plasticity in diabetes
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We previously reported enhanced cerebrovascular remodeling and arteriogenesis in experimental type 2 diabetes. This study tested the hypotheses: 1) cerebral but not peripheral angiogenesis is increased in a spatial manner, and 2) peroxynitrite orchestrates VEGF-mediated brain angiogenesis in diabetes. Stereology of brain, eye and skeletal muscle microvasculature was evaluated in control and diabetic rats using 3-D images. Migration and tube formation properties of brain microvascular endothelial cells (BMEC) were analyzed as markers of angiogenesis. Vascular density, volume and surface area were progressively increased from rostral to caudal sections in both cerebral cortex and striatum in diabetic rats. Unperfused new vessels were more prominent and pericyte/endothelial cell ratio was decreased in diabetes. Vascularization was greater in the retina but lower in the peripheral circulation. VEGF and nitrotyrosine levels were higher in cerebral microvessels of diabetic animals. Migratory and tube formation properties were enhanced in BMECs from diabetic rats which also expressed high levels of basal VEGF, nitrotyrosine and membrane type matrix metalloprotease (MT1-MMP). VEGF neutralizing antibody and inhibitors of peroxynitrite, src kinase or MMP blocked the migration. Diabetes increases and spatially regulates cerebral neovascularization. Increased VEGF-dependent angiogenic function in BMEC is mediated by peroxynitrite and involves c-src and MT1-MMP activation.