Astrocyte Involvement in Blood–Brain Barrier Function: A Critical Update Highlighting Novel, Complex, Neurovascular Interactions
Abstract
:1. Introduction
2. BBB Permeability-Regulating Proteins
3. Endothelial Cells Interplay with Astrocytes within the Neurovascular Unit (NVU)
3.1. Astrocytic Factors Supporting BBB Integrity
3.2. Astrocyte-Derived Factors Increasing BBB Permeability
4. Reactive Astrogliosis in BBB Dysfunction
5. Astrocyte Functional Identity Is Driven by Transcriptional and Epigenetic Changes
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
ACE-1 | Angiotensin converting enzyme-1 |
AHR | Aryl hydrocarbon receptor |
AJ | Adherens junction |
AKT (PKB) | Protein kinase B |
AMPA | α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid |
ANG-1/2 | Angiopoetin-1/2 |
ApoE | Apolipoprotein E |
ATAC-seq | Transposase accessible chromatin sequencing |
BAFF | B cell activating factor of the TNF family |
BBB | Blood–brain barrier |
BCR | B-cell receptor |
BDNF | Brain-derived neurotrophic factor |
BM | Basement membrane |
CCL | Chemokine ligand |
CD | Cluster of differentiation |
CNS | Central nervous system |
DhH | Desert Hedgehog |
DNA | Deoxyribonucleic acid |
ECs | Endothelial cells |
ECM | Extracellular matrix |
eNOS | Endothelial nitric oxide synthase |
ER | Endoplasmic reticulum |
ERK | Extracellular signal-regulated kinase |
ET | Endothelin |
ETR | Endothelin receptor |
FGF | Fibroblast Growth Factor |
GDNF | Glial-derived Neurotrophic Factor |
cGMP | Cyclic guanosine monophosphate |
GTP | Guanosine-5′-triphosphate |
HAT | Histone acetyltransferase |
HDAC | Histone deacetylases |
HDM | Histone demethylase |
HMT | Histone methyltransferase |
ICAM-1 | Intercellular adhesion molecule -1 |
IFN | Interferon |
IGF-1 | Insulin-Like Growth Factor |
IKK | IkappaB kinase |
IL | Interleukin |
IRAK | Interleukin-1 receptor-associated kinase |
IRF-1 | Interferon regulatory factor-1 |
JAK | Janus kinase |
HIF | Hypoxia-inducible factor |
HMGB1 | High mobility group box 1 protein |
LaST | Large-area spatial transcriptomic |
LIF | Leukemia inhibitory factor |
LPS | Lipopolysaccharide |
LRP1 | Low density lipoprotein receptor-related protein 1 |
MAP | Mitogen-activated protein |
MLC | Myosin light chain |
MLCK | Myosin light chain kinase |
MMP | Matrix metalloproteinase |
mRNA | Messenger ribonucleic acid |
miRNA | Micro ribonucleic acid |
MRP | miRNAs after myeloid-related protein |
NFAT | Nuclear factor of activated T-cells |
NF-kB | Nuclear Factor kappa-light-chain-enhancer of activated B cells |
NMDA | N-methyl-D-aspartate |
NO | Nitric oxide |
NVU | Neurovascular unit |
PAK | Src–Rac1–p21-activated kinase |
PHD2 | Prolyl hydroxylase domain protein 2 |
PI3K | Phosphoinositide3 kinase |
PK | Protein kinase |
PL | Phospholipase |
PTPN-2 | protein tyrosine phosphatase non-receptor type 2 |
RA | Retinoic acid |
RAGE | Advanced glycation end products |
RNAs | Ribonucleic acids |
ROS | Reactive oxygen species |
ROCK | Rho-associated protein kinase |
RRBS | Reduced representation bisulfite sequencing |
scRNA-seq | Single cell RNA sequencing |
snRNA-seq | Single nucleus RNA sequencing |
STAT3 | Signal transducer and activator of transcription 3 |
Smo | Signal transducer Smoothened |
smFISH | Single-molecule fluorescent in situ hybridization |
SOCS | Suppressor of cytokine signaling 1 |
SHh | Sonic Hedgehog |
TAK | TGFβ-activated kinase 1 |
TCR | T-cell receptor |
TGF-β | Transforming Growth Factor-β |
TJ | Tight junction |
TLR | Toll-like receptor |
TNF | Tumor Necrosis Factor |
VCAM-1 | Vascular cell adhesion molecule |
VE | Vascular endothelial |
VEGF | Vascular Endothelial Growth Factor |
ZO | Zonula occludens |
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Factors Promoting BBB Integrity | Mechanism of Action in Brain ECs | References |
---|---|---|
Sonic Hedgehog | Activates PTCH1 and SMO followed by GLI1 nuclear translocation. Increases expression of junctional proteins claudin-3, -5, occludin, junction adhesion molecule-A, VE-cadherin, p120, and laminin expression. Decreases the level of microglial TNF-α, IL-6, and IL-1β, CCL2, and of ICAM-1 in ECs. | [23,24,27,28,30,85] |
Angiopoetin-1 | Binds on angiopoietin-1 receptor Tie2, activation of PI3K /AKT-myocyte enhancer factor-2 (MEF2)-Krüppel-like factor 2 (KLF2) pathway stabilizes TJ and AJ. Counteracts VEGF-induced endothelial permeability by inhibiting phosphorylation of VE-cadherin. Up-regulates occludin and ZO-1 expression and prevents occludin phosphorylation, favoring occludin interaction with ZO-1. Suppresses VEGF-induced expression of ICAM-1 and VCAM-1. | [33,34,35,36,37,38,39] |
Retinoic acid | Interacts with RAR in ECs, interferes with ShH and Wnt pathways. Increases expression of ZO-1, occludin, claudin-5, and VE-cadherin. Activates nuclear factor erythroid 2-related factor 2 (NRF2) pathway, which results in ICAM-1 and VCAM-1 decreased expression in BMECs. | [43,44,45,46,47,48,81] |
Wnt Growth Factors | WNT/β-catenin pathway activation and nuclear translocation of β-catenin increase endothelial expression of claudin-3, claudin-5, and occludin reducing BBB permeability. Decrease caveolin-1 expression and decreased transcellular vesicular traffic in brain ECs. | [49,50,86] |
Glial-derived Neurotrophic Factor | Binds on GDNF family receptor α1 and RET receptor kinase, activates sirtuin 1/ eNOS, PI3K/Akt, cAMP/PKA pathway and inactivates p38 MAPK, preventing TJ protein degradation; increases claudin-5, occludin and ZO-1 expression. | [52,53,54] |
Fibroblast Growth Factor | Binds to FGFR1 and activates S1PR1, ERK, and PI3K/AKT/Rac-1 pathways preventing TJ and AJ proteins degradation. Increases astrocytic proliferation, influences astrocyte morphology. | [55,56,57,58,59,60,61] |
Apolipoprotein E3 | APOE4 binds on LRP1 in pericytes and induces MMP-9 secretion from pericyte via CypA/NFκB pathway. ApoE3 counteracts BBB disruption through MMP-9 activation by ApoE4. | [62,63,64] |
Factors promoting BBB permeability | ||
Vascular Endothelial Growth Factor (VEGF) | Activation of nuclear factor κB (NF-κB) by TLRs and RAGE or activation of JAK2/STAT3/ HIF1α pathway are involved in VEGF production in astrocytes. Activation of HIF1α/VEGF/VEGFR2/ERK pathway is involved in the TNF-α-induced down-regulation of TJ proteins. IL-1β induces HIF1α-mediated VEGF expression. VEGF signaling increases BBB permeability through PI3K/Akt/eNOS, PLCγ/ PKC/ ERK, p38, and Src pathways, resulting in TJ-related protein down-regulation (occludin and claudin-5) and eNOS up-regulation. VEGF induces expressions of ICAM-1, VCAM-1, and MMP-9. eNOS activation and NO produce TJ and AJ complex disruption. Activation of Src and focal adhesion kinase result in phosphorylation and internalization of the VE-Cadherin and AJ breakdown. | [40,65,66,67,68,69,70] |
Nitric oxide (NO) Reactive oxygen species (ROS) | NO production in reactive astrocytes after iNOS up-regulation is followed by activation of GMP/PKG and endothelial TJ protein down-regulation. ROS lead to arachidonic acids-mediated MMP activation and increased cytokine production. ROS induce down-regulation and degradation of TJ-related proteins through activation of the ROCK /MLC /MLCK pathway. | [61,80,86,87,88,89] |
Matrix metalloproteinases (MMPs) | MMPs degrade the extracellular matrix proteins (collagen, fibronectin, and laminin), and TJ-related proteins. Astrocytic MMP-2 and MMP-9 stimulate NF-κB activation, leading to chemokine expression. | [61,72,73,74,75,76,77,90] |
Glutamate | Decreased glutamate reuptake in reactive astrocytes results in excessive extracellular glutamate and increased MMP-2 and MMP-9 expression. | [71,77,78,86] |
Endothelins (ETs) and other vasoactive mediators | Endothelin-1 (ET-1), arachidonic acids, and arachidonic acids metabolite PGE2 are up-regulated in reactive astrocyte via PLA2 activation. PGE2 modulates BBB integrity and induces endothelial migration via cAMP/PKA pathway activation. Increased expression of ET-1 in reactive astrocytes impairs BBB integrity through endothelial MMP-2, -9, and VEGF up-regulation. ET-1 triggers astrocytic AQP4 down-regulation, and affects ECs contact with astrocytic end-feet. ET-1 binding on endothelial ET-A and ET-B results in NF-κB activation, vascular inflammation, increased PGE2 production via COX2 activation, and immune cell migration due to up-regulated ICAM-1, and VCAM-1, and E-selectin. | [79,80,81,82,83,84] |
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Manu, D.R.; Slevin, M.; Barcutean, L.; Forro, T.; Boghitoiu, T.; Balasa, R. Astrocyte Involvement in Blood–Brain Barrier Function: A Critical Update Highlighting Novel, Complex, Neurovascular Interactions. Int. J. Mol. Sci. 2023, 24, 17146. https://doi.org/10.3390/ijms242417146
Manu DR, Slevin M, Barcutean L, Forro T, Boghitoiu T, Balasa R. Astrocyte Involvement in Blood–Brain Barrier Function: A Critical Update Highlighting Novel, Complex, Neurovascular Interactions. International Journal of Molecular Sciences. 2023; 24(24):17146. https://doi.org/10.3390/ijms242417146
Chicago/Turabian StyleManu, Doina Ramona, Mark Slevin, Laura Barcutean, Timea Forro, Tudor Boghitoiu, and Rodica Balasa. 2023. "Astrocyte Involvement in Blood–Brain Barrier Function: A Critical Update Highlighting Novel, Complex, Neurovascular Interactions" International Journal of Molecular Sciences 24, no. 24: 17146. https://doi.org/10.3390/ijms242417146