Diabetes Metab J.  2022 Mar;46(2):222-238. 10.4093/dmj.2021.0146.

Glial and Vascular Cell Regulation of the Blood-Brain Barrier in Diabetes

• Li X
• Cai Y
• Zhang Z
• Zhou J

• KMID: 2527716
• DOI: http://doi.org/10.4093/dmj.2021.0146

Abstract

As a structural barrier, the blood-brain barrier (BBB) is located at the interface between the brain parenchyma and blood, and modulates communication between the brain and blood microenvironment to maintain homeostasis. The BBB is composed of endothelial cells, basement membrane, pericytes, and astrocytic end feet. BBB impairment is a distinguishing and pathogenic factor in diabetic encephalopathy. Diabetes causes leakage of the BBB through downregulation of tight junction proteins, resulting in impaired functioning of endothelial cells, pericytes, astrocytes, microglia, nerve/glial antigen 2-glia, and oligodendrocytes. However, the temporal regulation, mechanisms of molecular and signaling pathways, and consequences of BBB impairment in diabetes are not well understood. Consequently, the efficacy of therapies diabetes targeting BBB leakage still lags behind the requirements. This review summarizes the recent research on the effects of diabetes on BBB composition and the potential roles of glial and vascular cells as therapeutic targets for BBB disruption in diabetic encephalopathy.

Keyword

Astrocytes; Blood-brain barrier; Diabetes mellitus; Endothelial cells; Microglia; Oligodendrocyte precursor cells; Oligodendroglia; Pericytes

Figure

• 

  Fig. 1. The location and connection of glia (astrocytes, microglia, nerve/glial antigen 2 [NG2-glia], and oligodendrocytes) and vascular cells (endothelial cells and pericytes) in diabetic blood-brain barrier (BBB). As the major constituents of the BBB, endothelial cells connect via gap junctional proteins and works together with various other cell types, such as astrocytes, pericytes, microglia, NG2-glia, and oligodendrocytes. Their synergistic communication contributes to the functional properties of the BBB.

• 

  Fig. 2. The detrimental effects of diabetes on glia and vascular cells to increase blood-brain barrier (BBB) permeability. As a basic characteristic of diabetes, hyperglycemia function as the initiating injury factor of BBB leakage, and other injury factors induced by hyperglycemia further aggravate the damage of BBB, such as advanced glycation end-products, inflammation, oxidative stress, metalloproteinase, astrocyte apoptosis, microglia polarization to swallow astrocytic end-feet, nerve/glial antigen 2 (NG2-glia) proliferation, pericyte death, and lower endothelial tight junction coverage.

• 

  Fig. 3. Glial and vascular cell functions and mechanisms involved in diabetic blood-brain barrier (BBB) permeability. Astrocytes modulate diabetic BBB integrity via glial-derived neurotrophic factor, nitric oxide, tumor necrosis factor-α, reactive oxygen-nitrogen, advanced glycation end-products, transforming growth factor-β, glial cell line-derived neurotrophic factor, basic fibroblast growth factor, interleukin-6, steroids, the αvβ5-integrin/glycogen synthase kinase-3β/β-catenin signaling pathway, and noncanonical hedgehog signaling. Microglia regulate diabetic BBB integrity via claudin-5, cytokines, and chemokines. Nerve/glial antigen 2 (NG2-glia) cause diabetic BBB breakdown via metalloproteinase 9 secretion and protection via the transforming growth factor β-receptor-mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase signaling pathway. Oligodendrocytes improve diabetic BBB permeability through various soluble factors. Endothelial cells modulate BBB integrity via junction proteins, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, chemokine receptor, Calcium/calmodulin-dependent protein kinase kinase α and β, adenosine receptor 2a, the C3a/C3a receptor signaling pathway, and the fibroblast growth factor receptor 1/Kelch-like ECH-associating protein 1 (Keap1)/NF-E2 related factor-2 (Nrf2) activation pathway. Pericytes regulate BBB permeability via transforming growth factor-β, vascular endothelial growth factor, fibronectin, claudin-5, integrin α1, platelet-derived growth factors receptor-β1, connexin-43, monocyte chemoattractant protein-1, CCAAT/enhancer binding protein homologous protein, and transcription factor 4.

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