Abstract
BackgroundHyperglycemia has been recognized as a primary factor in endothelial barrier dysfunction and in the development of micro- and macrovascular diseases associated with diabetes, but the underlying biochemical mechanisms remain elusive. Tyrosine phosphorylation of vascular endothelial cadherin (VE-cad) leads to the disruption of endothelial adherens junctions and increases the transendothelial migration (TEM) of leukocytes.MethodsVE-cad tyrosine phosphorylation, adherens junction integrity and TEM of monocytes in human umbilical vein endothelial cells (HUVECs) treated with high-concentration glucose were evaluated. The role of protein kinase C (PKC) in induction of endothelial cells adherence junction disruption by exposure of HUVECs to high concentration of glucose was explored.ResultsThe treatment of HUVEC with high-concentration glucose increased VE-cad tyrosine phosphorylation, whereas mannitol or 3-O-methyl-D-glucose had no effect. In addition, high-concentration glucose increased the dissociation of the VE-cad–β-catenin complex, activation of the Wnt/β-catenin pathway, and the TEM of monocytes. These alterations were accompanied by the activation of endothelial PKC and increased phosphorylation of ERK and myosin light chain (MLC). High-concentration glucose-induced tyrosine phosphorylation of VE-cad was attenuated by: 1- the inhibition of PKC-β by overexpression of dominant-negative PKC-β 2- inhibition of MLC phosphorylation by overexpression of a nonphosphorylatable dominant-negative form of MLC, 3- the inhibition of actin polymerization by cytochalasin D and 4- the treatment of HUVECs with forskolin (an activator of adenylate cyclase).ConclusionsOur findings show that the high-concentration glucose-induced disruption of endothelial adherens junctions is mediated by tyrosine phosphorylation of VE-cad through PKC-β and MLC phosphorylation.
Highlights
Atherogenesis is a vascular inflammatory process characterized by the enhanced recruitment of leukocytes to dysfunctional endothelium [1]
Treatment of Endothelial Cells with High-Concentration Glucose Leads to the Disintegration of Endothelial adherens junctions (AJs) The treatment of human umbilical vein endothelial cells (HUVECs) with high concentrations of D-glucose, otherwise referred to as glucose, for 24 hours increased tyrosine phosphorylation of vascular endothelial cadherin (VE-cad) in a dosedependent manner (Figure 1A)
Similar to HUVECs treated with high concentrations of glucose, human aortic endothelial cells (HAECs) treated with high concentrations of glucose for 24 h showed a dose-dependent increase in VE-cad tyrosine phosphorylation (Figure 1H)
Summary
Atherogenesis is a vascular inflammatory process characterized by the enhanced recruitment of leukocytes to dysfunctional endothelium [1]. It has been demonstrated that high concentration of glucose mediates an increase in permeability of endothelial cells to albumin by activation of protein kinase C [15]. The integrity of AJs is a characteristic of endothelial barrier that regulates TEM of monocytes [6,7] and might be independent of permeability of endothelial cells to albumin. The molecular mechanisms underlying the effect of high concentration of glucose on integrity of endothelial AJs and TEM of monocytes has not been fully explored. We hypothesized that high concentrations of glucose disintegrate endothelial AJs and facilitate the TEM of monocytes through the protein kinase C-mediated tyrosine phosphorylation of VE-cad. Tyrosine phosphorylation of vascular endothelial cadherin (VE-cad) leads to the disruption of endothelial adherens junctions and increases the transendothelial migration (TEM) of leukocytes
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