Abstract
We have previously shown that diabetes causes dysfunctional cerebral neovascularization that increases the risk for cerebrovascular disorders such as stroke and cognitive impairment. Pericytes (PCs) play a pivotal role in the angiogenic process through their interaction with the endothelial cells (EC). Yet, the role of PCs in dysfunctional cerebral neovascularization in diabetes is unclear. In the present study, we tested the hypothesis that the increased proangiogenic Ephrin-B2 signaling in PCs contributes to the dysfunctional cerebral neovascularization in diabetes. Type-II diabetes was induced by a combination of high fat diet and low dose streptozotocin injection in male Wistar rats. Selective in vivo Ephrin-B2 silencing in brain PCs was achieved using the stereotactic injection of adeno-associated virus (AAV) with NG2-promoter that expresses Ephrin-B2 shRNA. Neovascularization was assessed using vascular fluorescent dye stain. Novel object recognition (NOR) test was used to determine cognitive functions. Human brain microvascular pericytes HBMVPCs were grown in high glucose 25 mM and palmitate 200 uM (HG/Pal) to mimic diabetic conditions. Scratch migration and tube formation assays were conducted to evaluate PC/EC interaction and angiogenic functions in PC/EC co-culture. Diabetes increased the expression of Ephrin-B2 in the cerebrovasculature and pericytes. Concomitant increases in cerebral neovascularization parameters including vascular density, tortuosity and branching density in diabetic rats were accompanied by deterioration of cognitive function. Inhibition of Ephrin-B2 expression in PCs significantly restored cerebral vascularization and improved cognitive functions. HG/Pal increased PC/EC angiogenic properties in co-culture. Silencing Ephrin-B2 in PCs significantly reduced PC migration and PC/EC co-culture angiogenic properties. This study emphasizes the significant contribution of PCs to the pathological neovascularization in diabetes. Our findings introduce Ephrin-B2 signaling as a promising therapeutic target to improve cerebrovascular integrity in diabetes.
Highlights
Diabetes causes devastating vascular complications such as diabetic retinopathy, stroke and cognitive impairment [1]
Our results showed a significant increase in Ephrin-B2 expression in the perivascular areas in the brain cortex that is co-localized with pericytes (Fig 1A and 1B)
We present new evidence that pericytes contribute to diabetes-induced cerebral pathological neovascularization
Summary
Diabetes causes devastating vascular complications such as diabetic retinopathy, stroke and cognitive impairment [1]. The cost for managing diabetes-induced vascular complications is rising every day in the United States and worldwide with the increasing numbers of diabetic patients [2, 3]. There is an urgent need to understand how diabetes affects the cerebral microvasculature, a common player in most diabetes-induced cerebral complications. Emerging evidence suggests that diabetes mediates pathological cerebrovascular neovascularization, which is correlated with cognitive dysfunction [4,5,6]. The purpose of the current study is to unravel the role of Ephrin-B2 signaling in pericytes as one of the signaling mechanisms that is involved in diabetes-mediated pathological cerebrovascular neovascularization
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