Dual Roles of Astrocyte-Derived Factors in Regulation of Blood-Brain Barrier Function after Brain Damage

Abstract

The blood-brain barrier (BBB) is a major functional barrier in the central nervous system (CNS), and inhibits the extravasation of intravascular contents and transports various essential nutrients between the blood and the brain. After brain damage by traumatic brain injury, cerebral ischemia and several other CNS disorders, the functions of the BBB are disrupted, resulting in severe secondary damage including brain edema and inflammatory injury. Therefore, BBB protection and recovery are considered novel therapeutic strategies for reducing brain damage. Emerging evidence suggests key roles of astrocyte-derived factors in BBB disruption and recovery after brain damage. The astrocyte-derived vascular permeability factors include vascular endothelial growth factors, matrix metalloproteinases, nitric oxide, glutamate and endothelin-1, which enhance BBB permeability leading to BBB disruption. By contrast, the astrocyte-derived protective factors include angiopoietin-1, sonic hedgehog, glial-derived neurotrophic factor, retinoic acid and insulin-like growth factor-1 and apolipoprotein E which attenuate BBB permeability resulting in recovery of BBB function. In this review, the roles of these astrocyte-derived factors in BBB function are summarized, and their significance as therapeutic targets for BBB protection and recovery after brain damage are discussed.

Keywords: astrocytes; blood-brain barrier; endothelial cells; tight junction.

Figure 1

The BBB comprises endothelial cells, pericytes and astrocytes. The low permeability to serum components results from dense formation of TJs between brain microvascular endothelial cells. TJs comprise TJ-related proteins including claudin-5, occludin and ZO-1. Astrocytes produce several factors that modulate the expression of the TJ-related proteins and regulate paracellular transport across vascular endothelial cells. In addition, astrocyte-derived factors affect the expression of endothelial ICAM-1 and VCAM-1, which interact with VLA-4 and LFA-1 in leukocytes. Increased ICAM-1 and VCAM-1 expression promotes leukocyte infiltration into the CNS.

Figure 2

Dual roles of astrocyte-derived factors in the regulation of BBB functions. In brain disorders, astrocytes release various kinds of extracellular signaling molecules. (A) Vascular permeability factors: Astrocyte-derived vascular endothelial growth factors (VEGFs), matrix metalloproteinases (MMPs), nitric oxide (NO), glutamate and endothelins (ETs) cause endothelial apoptosis and downregulation of TJ-related proteins, resulting in BBB disruption. Some of these factors also upregulate endothelial CAMs, which induce leukocyte transmigration. (B) Vascular protective factors: Astrocyte-derived angiopoietin-1 (ANG-1), sonic hedgehog (SHH), glial-derived neurotrophic factor (GDNF), retinoic acid (RA), insulin-like growth factor-1 (IGF-1) and apolipoprotein E (APOE) protect endothelial cells from apoptosis and promote recovery of TJ function. Some of these factors also decrease endothelial CAMs’ expression and reduce leukocyte infiltration.

Figure 3

Therapeutic strategy for BBB protection and recovery of BBB function by controlling the function of astrocyte-derived factors. Astrocytic estrogen receptor (ER), ET_B receptor (ET_BR), cannabinoid receptor (CBR) and microRNAs are involved in the regulation of astrocyte-derived factors production. Hence, these receptors and microRNAs are candidates for protection/recovery of BBB functions by modulating the actions of astrocyte-derived factors.