Abstract
In the diabetic brain, hyperglycemia damages the cerebrovasculature and impairs neurovascular crosstalk. Calcitonin gene-related peptide (CGRP) is an important neuropeptide that is active in the vascular system. In this study, we aimed to investigate whether CGRP is involved in the high-glucose-induced damage in mouse cerebral microvascular endothelial (b.END3) cells and the possible mechanism in vitro. The overexpression of CGRP by lentiviral transduction inhibited cell apoptosis but not proliferation. In contrast to the promoting of angiogenesis and migration under normal glucose, CGRP inhibited hyperglycemia-induced tube formation but had no effect on migration. Calcitonin gene-related peptide partly reduced the increased level of intracellular reactive oxygen species (ROS) and altered nitric oxide synthase mRNA expression. Furthermore, CGRP suppressed the increased HIF-1α/VEGF-A expression and the phosphorylation of ERK1/2 in hyperglycemia. The ERK inhibitor U0126 showed similar inhibition of cell apoptosis, tube formation and HIF-1α/VEGF expression as that exhibited by lenti-CGRP. These findings demonstrate the protective role of CGRP overexpression against high-glucose-induced cerebrovascular changes in b.END3 cells, possibly through the inhibition of ERK/HIF-1/VEGF signaling.
Highlights
Among the many complications of diabetes mellitus, vascular dysfunction plays a primary role and often begins with endothelial cell damage [1]
We investigated the effect of the overexpression of Calcitonin generelated peptide (CGRP) in mouse cerebral microvascular endothelial cells (b.END3) cells and whether it is associated with ERK/hypoxia inducible factor-1 (HIF-1)/vascular endothelial growth factor (VEGF) signaling
High glucose decreased the expression of the main CGRP receptor, and successful lentiviral transduction led to the stable overexpression of CGRP in b.END3 cells
Summary
Among the many complications of diabetes mellitus, vascular dysfunction plays a primary role and often begins with endothelial cell damage [1]. Diabetic endothelial cells exhibit a series of changes, such as reduced nitric oxide (NO) activity and increased cytokines and reactive oxygen species (ROS) levels, and oxidative stress plays a central role in these changes [2,3,4,5]. The major mechanisms underlying the changes in cerebral microvascular endothelial cells under high glucose remain unclear. The activation of ERK upregulates the expression of hypoxia inducible factor-1 (HIF-1) followed by vascular endothelial growth factor (VEGF), which are reported to be important regulators in diabetic cerebral microvascular endothelial cells [7, 13]. The increased expression of VEGF results in proliferative angiogenesis [13, 15]
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