Enhanced cerebral but not peripheral angiogenesis in the Goto-Kakizaki model of type 2 diabetes involves VEGF and peroxynitrite signaling

Roshini Prakash, Payaningal R. Somanath, Azza B. El-Remessy, Aisha Kelly-Cobbs, Javier Eduardo Stern, Paula Dore-Duffy, Maribeth H Johnson, Susan C. Fagan, Adviye Ergul

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1533-1542
Number of pages10
JournalDiabetes
Volume61
Issue number6
DOIs
StatePublished - Jun 1 2012

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Peroxynitrous Acid
Type 2 Diabetes Mellitus
Vascular Endothelial Growth Factor A
Metalloproteases
Endothelial Cells
Brain
Microvessels
Pericytes
Three-Dimensional Imaging
src-Family Kinases
Neutralizing Antibodies
Cerebral Cortex
Blood Vessels
Retina
Skeletal Muscle
Membranes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Prakash, R., Somanath, P. R., El-Remessy, A. B., Kelly-Cobbs, A., Stern, J. E., Dore-Duffy, P., ... Ergul, A. (2012). Enhanced cerebral but not peripheral angiogenesis in the Goto-Kakizaki model of type 2 diabetes involves VEGF and peroxynitrite signaling. Diabetes, 61(6), 1533-1542. https://doi.org/10.2337/db11-1528

Enhanced cerebral but not peripheral angiogenesis in the Goto-Kakizaki model of type 2 diabetes involves VEGF and peroxynitrite signaling. / Prakash, Roshini; Somanath, Payaningal R.; El-Remessy, Azza B.; Kelly-Cobbs, Aisha; Stern, Javier Eduardo; Dore-Duffy, Paula; Johnson, Maribeth H; Fagan, Susan C.; Ergul, Adviye.

In: Diabetes, Vol. 61, No. 6, 01.06.2012, p. 1533-1542.

Research output: Contribution to journalArticle

Prakash, R, Somanath, PR, El-Remessy, AB, Kelly-Cobbs, A, Stern, JE, Dore-Duffy, P, Johnson, MH, Fagan, SC & Ergul, A 2012, 'Enhanced cerebral but not peripheral angiogenesis in the Goto-Kakizaki model of type 2 diabetes involves VEGF and peroxynitrite signaling', Diabetes, vol. 61, no. 6, pp. 1533-1542. https://doi.org/10.2337/db11-1528
Prakash, Roshini ; Somanath, Payaningal R. ; El-Remessy, Azza B. ; Kelly-Cobbs, Aisha ; Stern, Javier Eduardo ; Dore-Duffy, Paula ; Johnson, Maribeth H ; Fagan, Susan C. ; Ergul, Adviye. / Enhanced cerebral but not peripheral angiogenesis in the Goto-Kakizaki model of type 2 diabetes involves VEGF and peroxynitrite signaling. In: Diabetes. 2012 ; Vol. 61, No. 6. pp. 1533-1542.
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