Adaptive Cerebral Neovascularization in a Model of Type 2 Diabetes

Abstract

OBJECTIVEThe effect of diabetes on neovascularization varies between different organ systems. While excessive angiogenesis complicates diabetic retinopathy, impaired neovascularization contributes to coronary and peripheral complications of diabetes. However, how diabetes influences cerebral neovascularization is not clear. Our aim was to determine diabetes-mediated changes in the cerebrovasculature and its impact on the short-term outcome of cerebral ischemia.RESEARCH DESIGN AND METHODSAngiogenesis (capillary density) and arteriogenesis (number of collaterals and intratree anostomoses) were determined as indexes of neovascularization in the brain of control and type 2 diabetic Goto-Kakizaki (GK) rats. The infarct volume, edema, hemorrhagic transformation, and short-term neurological outcome were assessed after permanent middle–cerebral artery occlusion (MCAO).RESULTSThe number of collaterals between middle and anterior cerebral arteries, the anastomoses within middle–cerebral artery trees, the vessel density, and the level of brain-derived neurotrophic factor were increased in diabetes. Cerebrovascular permeability, matrix metalloproteinase (MMP)-9 protein level, and total MMP activity were augmented while occludin was decreased in isolated cerebrovessels of the GK group. Following permanent MCAO, infarct size was smaller, edema was greater, and there was no macroscopic hemorrhagic transformation in GK rats.CONCLUSIONSThe augmented neovascularization in the GK model includes both angiogenesis and arteriogenesis. While adaptive arteriogenesis of the pial vessels and angiogenesis at the capillary level may contribute to smaller infarction, changes in the tight junction proteins may lead to the greater edema following cerebral ischemia in diabetes.

Illuminating the Effects of Stroke on the Diabetic Brain: Insights From Imaging Neural and Vascular Networks in Experimental Animal Models

“…Many studies have examined the effects of diabetes on BBB function (45) and its response to stroke. The results have been in striking agreement, showing that diabetes exacerbates the disruption of the BBB (15,38). By using the STZ model of T1D, our group and others (8,10,15) have demonstrated that diabetic mice exhibit significantly greater hemorrhage volume and extravasation of blood-borne dyes in peri-infarct cortex 1-3 days after stroke (Fig.…”

“…2G and I). Although this finding may seem counterintuitive, a study by Li et al (38) that used laser Doppler imaging for regional estimates of cerebral blood flow also showed elevated blood flow 24 h after stroke in the GK T2D rat. In the Tennant and Brown study, administration of insulin to hyperglycemic mice immediately after stroke provided only a partial normalization of blood velocity levels (Fig.…”

Surgical outcomes following encephaloduroarteriosynangiosis in adult moyamoya disease associated with Type 2 diabetes

“…Li et al had confirmed that angiogenesis and arteriogenesis showed remarkable increases in the number of collaterals, the diameters of the collaterals, the number of anastomoses, and microvessel density in T2DM Goto-Kakizaki rats. 16 The experimental results revealed a significant rise in the level of vascular endothelial growth factor (VEGF) and nitrotyrosine. 24 The levels of growth factors and cytokines that were regarded as important in the development of sprouting collateral vessels from the extracranial vascular system by indirect revascularization, such as the expression of VEGF, basic fibroblast growth factor, transforming growth factorb, granulocyte colony-stimulating factor, and hepatocyte growth factor, have been proven to be elevated in many studies in MMD patients.…”

Cerebral Neovascularization in Diabetes: Implications for Stroke Recovery and beyond

“…We have shown that diabetes causes increased, yet dysfunctional, neovascularization in the cerebrovasculature. [30][31][32] There is increased arteriogenesis (greater number of collaterals and increased vascular tortuosity) in the pial vasculature of type 2 diabetic Goto-Kakizaki (GK) rats. 30 A follow-up study provided evidence for increased cerebral angiogenesis and arteriogenesis.…”