Enhanced Cerebral but Not Peripheral Angiogenesis in the Goto-Kakizaki Model of Type 2 Diabetes Involves VEGF and Peroxynitrite Signaling

被引：105

作者：

Prakash, Roshini ^{[1
,2
]}

Somanath, Payaningal R. ^{[1
,2
]}

El-Remessy, Azza B. ^{[1
,2
]}

Kelly-Cobbs, Aisha ^{[3
]}

Stern, Javier E. ^{[3
]}

Dore-Duffy, Paula ^{[4
]}

Johnson, Maribeth ^{[5
]}

Fagan, Susan C. ^{[1
,2
]}

Ergul, Adviye ^{[1
,2
,3
]}

机构：

[1] Univ Georgia, Coll Pharm, Charlie Norwood Vet Adm Med Ctr, Athens, GA 30602 USA

[2] Univ Georgia, Coll Pharm, Program Clin & Expt Therapeut, Athens, GA 30602 USA

[3] Georgia Hlth Sci Univ, Dept Physiol, Augusta, GA USA

[4] Wayne State Univ, Sch Med, Dept Neurol, Detroit, MI 48201 USA

[5] Georgia Hlth Sci Univ, Dept Biostat, Augusta, GA USA

来源：

DIABETES | 2012年 / 61卷 / 06期

基金：

美国国家卫生研究院;

关键词：

ENDOTHELIAL GROWTH-FACTOR; CORONARY COLLATERAL GROWTH; BLOOD-RETINAL BARRIER; MATRIX METALLOPROTEINASES; MICROVASCULAR PERICYTES; OXIDATIVE STRESS; GLYCEMIC CONTROL; RETINOPATHY; CELLS; COMPLICATIONS;

D O I：

10.2337/db11-1528

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

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 rnicrovasculature 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. Diabetes 61:1533-1542, 2012

引用

页码：1533 / 1542

页数：10

共 49 条

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