Linagliptin attenuates diabetes-induced cerebral pathological neovascularization in a blood glucose-independent manner: Potential role of ET-1

Abstract

Aims We have shown that glycemic control with metformin or endothelin-1 (ET-1) inhibition with bosentan prevents and restores diabetes-mediated cerebral pathological remodeling and neovascularization. Our recent data suggest that linagliptin, a member of the dipeptidyl peptidase-4 inhibitor class of glucose-lowering agents, prevents cerebrovascular remodeling and dysfunction independent of its blood glucose lowering effects. We hypothesized that linagliptin prevents pathological neovascularization via the modulation of the ET-1 system. Materials and Methods 24-week old diabetic Goto-Kakizaki and nondiabetic Wistar rats were treated for 4 weeks with either vehicle chow or chow containing 166mg/kg linagliptin. At termination, FITC-dextran was injected to visualize the vasculature. Brain sections were imaged by confocal microscopy for vascular density, tortuosity, vascular volume, and surface in both the cortex and striatum. Retinal acellular capillary formation was measured. Brain microvascular endothelial cells (BMVEC) isolated from control or diabetic rats were treated with linagliptin with or without ET-1 dual receptor antagonist and tested for angiogenic properties with cell migration and tube formation assays. Key Finding Linagliptin reduced all indices of cerebral neovascularization compared with control rats. In vitro, linagliptin normalized the augmented angiogenic properties of BMVECs isolated from diabetic animals and bosentan reversed this response. Cells from diabetic animals had higher ET-1 and less ETB receptors than in control cells. Linagliptin significantly decreased ET-1 levels and increased ETB receptors. Significance ET system contributes to pathological neovascularization in diabetes as evidenced by restoration of functional angiogenesis by bosentan treatment and prevention of linagliptin-mediated improvement of angiogenesis in the in vitro model.

NLRP3 inflammasome inhibition with MCC950 improves diabetes-mediated cognitive impairment and vasoneuronal remodeling after ischemia

“…Hippocampal vascular networks were visualized with the space-filling FITC-dextran injection method, as we previously described [46,47]. Volocity software was used to measure vascular volume and surface area, while Fiji was used to measure branch density.…”

Poststroke cognitive impairment and hippocampal neurovascular remodeling: the impact of diabetes and sex

“…Vascular indexes. Vascular networks in the hippocampus were visualized with the space-filling FITC-dextran injection method, as we have previously reported (1,40). Briefly, rats were anesthetized and injected through the jugular vein with high-molecular-weight FITCdextran (molecular weight: 2,000,000, Sigma-Aldrich, St. Louis, MO) 10 min before euthanasia.…”

Endothelin and Diabetic Complications: a Brain-Centric View

“…Moreover, linagliptin normalizes the augmented angiogenic properties of brain microvascular endothelial cells isolated from diabetic animals and bosentan blocks this response. While linagliptin significantly decreases ET-1 levels, it increases ET B receptors (Abdelsaid et al 2016). ET A receptor antagonism has been shown to reduce string vessels and neuronal death in a diabetic retinopathy model providing additional evidence that ET receptor blockade is neurovascular protective in diabetes (Chou et al 2014).…”