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

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2019 Feb 1

PMID 30699952

Citations 120

Authors

Shotaro Michinaga

Yutaka Koyama

Affiliations

Soon will be listed here.

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.

Citing Articles

The blood-brain barriers: novel nanocarriers for central nervous system diseases.

Liu J, Wang T, Dong J, Lu Y J Nanobiotechnology. 2025; 23(1):146.

PMID: 40011926 PMC: 11866817. DOI: 10.1186/s12951-025-03247-8.

The Secretome of Brain Endothelial Cells Exposed to the Pyrrolizidine Alkaloid Monocrotaline Induces Astrocyte Reactivity and Is Neurotoxic.

Santos L, Borges J, Leite J, Victor M, da Silva A, Dos Santos C Toxins (Basel). 2025; 17(2).

PMID: 39998082 PMC: 11860515. DOI: 10.3390/toxins17020065.

The Flavonoid Agathisflavone Attenuates Glia Activation After Mechanical Injury of Cortical Tissue and Negatively Regulates Both NRLP3 and IL-1β Expression.

de Sousa V, Almeida A, Ferreira R, Dos Santos B, da Silva V, David J Int J Mol Sci. 2025; 26(3).

PMID: 39941042 PMC: 11818122. DOI: 10.3390/ijms26031275.

The Role of Neuroglia in the Development and Progression of Schizophrenia.

Rawani N, Chan A, Todd K, Baker G, Dursun S Biomolecules. 2025; 15(1).

PMID: 39858403 PMC: 11761573. DOI: 10.3390/biom15010010.

Evaluation of Plasma Neurodegenerative Biomarkers for Diagnosing Minimal Hepatic Encephalopathy and Predicting Overt Hepatic Encephalopathy in Chinese Patients with Hepatic Cirrhosis.

Cheng Q, Liu Y, Yang Z, Zhang M, Liu T, Niu Y J Clin Transl Hepatol. 2025; 13(1):35-46.

PMID: 39801785 PMC: 11712093. DOI: 10.14218/JCTH.2024.00413.

References

Liu B, Neufeld A . Expression of nitric oxide synthase-2 (NOS-2) in reactive astrocytes of the human glaucomatous optic nerve head. Glia. 2000; 30(2):178-86. DOI: 10.1002/(sici)1098-1136(200004)30:2<178::aid-glia7>3.0.co;2-c. View

Utsumi H, Chiba H, Kamimura Y, Osanai M, Igarashi Y, Tobioka H . Expression of GFRalpha-1, receptor for GDNF, in rat brain capillary during postnatal development of the BBB. Am J Physiol Cell Physiol. 2000; 279(2):C361-8. DOI: 10.1152/ajpcell.2000.279.2.C361. View

Igarashi Y, Chiba H, Utsumi H, Miyajima H, Ishizaki T, Gotoh T . Expression of receptors for glial cell line-derived neurotrophic factor (GDNF) and neurturin in the inner blood-retinal barrier of rats. Cell Struct Funct. 2000; 25(4):237-41. DOI: 10.1247/csf.25.237. View

Rancan M, Otto V, Hans V, Gerlach I, Jork R, Trentz O . Upregulation of ICAM-1 and MCP-1 but not of MIP-2 and sensorimotor deficit in response to traumatic axonal injury in rats. J Neurosci Res. 2001; 63(5):438-46. DOI: 10.1002/1097-4547(20010301)63:5<438::AID-JNR1039>3.0.CO;2-P. View

Matsuo Y, Mihara Si , Ninomiya M, Fujimoto M . Protective effect of endothelin type A receptor antagonist on brain edema and injury after transient middle cerebral artery occlusion in rats. Stroke. 2001; 32(9):2143-8. DOI: 10.1161/hs0901.94259. View

Kim I, Moon S, Park S, Chae S, Koh G . Angiopoietin-1 reduces VEGF-stimulated leukocyte adhesion to endothelial cells by reducing ICAM-1, VCAM-1, and E-selectin expression. Circ Res. 2001; 89(6):477-9. DOI: 10.1161/hh1801.097034. View

Asahi M, Wang X, Mori T, Sumii T, Jung J, Moskowitz M . Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood-brain barrier and white matter components after cerebral ischemia. J Neurosci. 2001; 21(19):7724-32. PMC: 6762894. View

Zhang Z, Zhang L, Croll S, Chopp M . Angiopoietin-1 reduces cerebral blood vessel leakage and ischemic lesion volume after focal cerebral embolic ischemia in mice. Neuroscience. 2002; 113(3):683-7. DOI: 10.1016/s0306-4522(02)00175-6. View

Petrov T, Steiner J, Braun B, Rafols J . Sources of endothelin-1 in hippocampus and cortex following traumatic brain injury. Neuroscience. 2002; 115(1):275-83. DOI: 10.1016/s0306-4522(02)00345-7. View

10.

Rogers S, Peters C, Pomonis J, Hagiwara H, Ghilardi J, Mantyh P . Endothelin B receptors are expressed by astrocytes and regulate astrocyte hypertrophy in the normal and injured CNS. Glia. 2003; 41(2):180-90. DOI: 10.1002/glia.10173. View

11.

Fee D, Crumbaugh A, Jacques T, Herdrich B, Sewell D, Auerbach D . Activated/effector CD4+ T cells exacerbate acute damage in the central nervous system following traumatic injury. J Neuroimmunol. 2003; 136(1-2):54-66. DOI: 10.1016/s0165-5728(03)00008-0. View

12.

Narushima I, Kita T, Kubo K, Yonetani Y, Momochi C, Yoshikawa I . Highly enhanced permeability of blood-brain barrier induced by repeated administration of endothelin-1 in dogs and rats. Pharmacol Toxicol. 2003; 92(1):21-6. DOI: 10.1034/j.1600-0773.2003.920104.x. View

13.

Lee K, Jin S, Kim H, Lee Y . Matrix metalloproteinase inhibitor regulates inflammatory cell migration by reducing ICAM-1 and VCAM-1 expression in a murine model of toluene diisocyanate-induced asthma. J Allergy Clin Immunol. 2003; 111(6):1278-84. DOI: 10.1067/mai.2003.1501. View

14.

Lee S, Kim W, Choi Y, Song H, Son M, Gelman I . SSeCKS regulates angiogenesis and tight junction formation in blood-brain barrier. Nat Med. 2003; 9(7):900-6. DOI: 10.1038/nm889. View

15.

Sharp C, Hines I, Houghton J, Warren A, Jackson 4th T, Jawahar A . Glutamate causes a loss in human cerebral endothelial barrier integrity through activation of NMDA receptor. Am J Physiol Heart Circ Physiol. 2003; 285(6):H2592-8. DOI: 10.1152/ajpheart.00520.2003. View

16.

Shore P, Jackson E, Wisniewski S, Clark R, Adelson P, Kochanek P . Vascular endothelial growth factor is increased in cerebrospinal fluid after traumatic brain injury in infants and children. Neurosurgery. 2004; 54(3):605-11. DOI: 10.1227/01.neu.0000108642.88724.db. View

17.

Wilhelmsson U, Li L, Pekna M, Berthold C, Blom S, Eliasson C . Absence of glial fibrillary acidic protein and vimentin prevents hypertrophy of astrocytic processes and improves post-traumatic regeneration. J Neurosci. 2004; 24(21):5016-21. PMC: 6729371. DOI: 10.1523/JNEUROSCI.0820-04.2004. View

18.

Koistinaho M, Lin S, Wu X, Esterman M, Koger D, Hanson J . Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-beta peptides. Nat Med. 2004; 10(7):719-26. DOI: 10.1038/nm1058. View

19.

Lee S, Lo E . Induction of caspase-mediated cell death by matrix metalloproteinases in cerebral endothelial cells after hypoxia-reoxygenation. J Cereb Blood Flow Metab. 2004; 24(7):720-7. DOI: 10.1097/01.WCB.0000122747.72175.47. View

20.

Ardelt A, McCullough L, Korach K, Wang M, Munzenmaier D, Hurn P . Estradiol regulates angiopoietin-1 mRNA expression through estrogen receptor-alpha in a rodent experimental stroke model. Stroke. 2005; 36(2):337-41. DOI: 10.1161/01.STR.0000153795.38388.72. View