Enhanced Cerebral but Not Peripheral Angiogenesis in the Goto-Kakizaki Model of Type 2 Diabetes Involves VEGF and Peroxynitrite Signaling
- Roshini Prakash1,2,
- Payaningal R. Somanath1,2,
- Azza B. El-Remessy1,2,
- Aisha Kelly-Cobbs3,
- Javier E. Stern3,
- Paula Dore-Duffy4,
- Maribeth Johnson5,
- Susan C. Fagan1,2 and
- Adviye Ergul1,2,3⇓
- 1Charlie Norwood Veterans Administration Medical Center, University of Georgia College of Pharmacy, Athens, Georgia
- 2Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Athens, Georgia
- 3Department of Physiology, Georgia Health Sciences University, Augusta, Georgia
- 4Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan
- 5Department of Biostatistics, Georgia Health Sciences University, Augusta, Georgia
- Corresponding author: Adviye Ergul, .
We previously reported enhanced cerebrovascular remodeling and arteriogenesis in experimental type 2 diabetes. This study tested the hypotheses that 1) cerebral but not peripheral angiogenesis is increased in a spatial manner and 2) peroxynitrite orchestrates vascular endothelial growth factor (VEGF)-mediated brain angiogenesis in diabetes. Stereology of brain, eye, and skeletal muscle microvasculature was evaluated in control and diabetic rats using three-dimensional images. Migration and tube formation properties of brain microvascular endothelial cells (BMECs) were analyzed as markers of angiogenesis. Vascular density, volume, and surface area were progressively increased from rostral to caudal sections in both the cerebral cortex and striatum in diabetic rats. Unperfused new vessels were more prominent and the pericyte–to–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 (MT1) matrix metalloprotease (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 BMECs is mediated by peroxynitrite and involves c-src and MT1-MMP activation.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db11-1528/-/DC1.
- Received November 1, 2011.
- Accepted January 31, 2012.
- © 2012 by the American Diabetes Association.
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