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Abstract
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<h5 class="section-title" id="d8053931e147">Aims</h5>
<p id="P1">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.
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<h5 class="section-title" id="d8053931e152">Materials and Methods</h5>
<p id="P2">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.
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<h5 class="section-title" id="d8053931e157">Key Finding</h5>
<p id="P3">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 ET
<sub>B</sub> receptors than in control cells. Linagliptin significantly decreased
ET-1 levels
and increased ET
<sub>B</sub> receptors.
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<h5 class="section-title" id="d8053931e168">Significance</h5>
<p id="P4">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
<i>in vitro</i> model.
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