Sphingosine-1-phosphate Protects Against Brain Microvascular Endothelial Junctional Protein Disorganization and Barrier Dysfunction Caused by Alcohol

Overview

Journal Microcirculation

Specialties Biology
Cardiology & Vascular Diseases

Date 2018 Oct 4

PMID 30281888

Citations 10

Authors

Natascha G Alves

Sarah Y Yuan

Jerome W Breslin

Affiliations

Soon will be listed here.

Abstract

Objective: S1P has known endothelial barrier-protective properties, but whether this extends to the BBB is unclear. We hypothesized that alcohol-induced disruption of brain microvascular endothelial barrier function and junctional protein organization can be ameliorated by S1P treatment.

Methods: Cultured primary HBMEC monolayers were used to characterize endothelial-specific mechanisms of BBB regulation. TER and apparent permeability coefficients for albumin, dextran-4 kDa, and sodium fluorescein were used as indices of barrier function. Junctional localization of Claudin-5, VE-cadherin, and β-catenin was determined by immunofluorescence confocal microscopy. S1P was applied following treatment with alcohol.

Results: Alcohol significantly impaired HBMEC TER. Application of S1P after alcohol treatment resulted in a hastened recovery to the baseline HBMEC TER. Alcohol-treated HBMEC had a significantly higher mean permeability than control that was reversed by S1P. Alcohol caused the formation of gaps between cells. Treatment with S1P (after alcohol) increased junctional localization of VE-Cadherin, Claudin-5, and β-catenin.

Conclusions: Alcohol impairs the barrier function and junctional organization of HBMEC monolayers. S1P enhanced barrier function and restored junctions in the presence of alcohol, and thus may be useful for restoring BBB function during alcohol intoxication.

Citing Articles

Endothelial Homeostasis Under the Influence of Alcohol-Relevance to Atherosclerotic Cardiovascular Disease.

Gusti Y, Liu W, Athar F, Cahill P, Redmond E Nutrients. 2025; 17(5).

PMID: 40077672 PMC: 11901717. DOI: 10.3390/nu17050802.

Neutrophil Extracellular Traps Affect Human Inner Ear Vascular Permeability.

Sekulic M, Giaglis S, Chatelain N, Bodmer D, Petkovic V Int J Mol Sci. 2024; 25(18).

PMID: 39337254 PMC: 11431685. DOI: 10.3390/ijms25189766.

Determination of Solute Permeability of Microvascular Endothelial Cell Monolayers In Vitro.

Breslin J, Yuan S Methods Mol Biol. 2023; 2711:1-12.

PMID: 37776444 PMC: 10928851. DOI: 10.1007/978-1-0716-3429-5_1.

Endothelial mechanisms for inactivation of inflammation-induced hyperpermeability.

Nepali P, Burboa P, Lillo M, Mujica P, Iwahashi T, Zhang J Am J Physiol Heart Circ Physiol. 2023; 324(5):H610-H623.

PMID: 36867447 PMC: 10069978. DOI: 10.1152/ajpheart.00543.2022.

The Microvascular-Lymphatic Interface and Tissue Homeostasis: Critical Questions That Challenge Current Understanding.

Lampejo A, Jo M, Murfee W, Breslin J J Vasc Res. 2022; 59(6):327-342.

PMID: 36315992 PMC: 9780194. DOI: 10.1159/000525787.

References

Breslin J, Yuan S . Involvement of RhoA and Rho kinase in neutrophil-stimulated endothelial hyperpermeability. Am J Physiol Heart Circ Physiol. 2003; 286(3):H1057-62. DOI: 10.1152/ajpheart.00841.2003. View

Giaever I, Keese C . Micromotion of mammalian cells measured electrically. Proc Natl Acad Sci U S A. 1991; 88(17):7896-900. PMC: 52411. DOI: 10.1073/pnas.88.17.7896. View

Doggett T, Tur J, Alves N, Yuan S, Tipparaju S, Breslin J . Assessment of Cardiovascular Function and Microvascular Permeability in a Conscious Rat Model of Alcohol Intoxication Combined with Hemorrhagic Shock and Resuscitation. Methods Mol Biol. 2018; 1717:61-81. PMC: 5874498. DOI: 10.1007/978-1-4939-7526-6_6. View

Lippai D, Bala S, Petrasek J, Csak T, Levin I, Kurt-Jones E . Alcohol-induced IL-1β in the brain is mediated by NLRP3/ASC inflammasome activation that amplifies neuroinflammation. J Leukoc Biol. 2013; 94(1):171-82. PMC: 3685015. DOI: 10.1189/jlb.1212659. View

Amasheh S, Schmidt T, Mahn M, Florian P, Mankertz J, Tavalali S . Contribution of claudin-5 to barrier properties in tight junctions of epithelial cells. Cell Tissue Res. 2005; 321(1):89-96. DOI: 10.1007/s00441-005-1101-0. View

Sharma S, Mathur A, Pradhan S, Singh D, Gupta S . Fingolimod (FTY720): First approved oral therapy for multiple sclerosis. J Pharmacol Pharmacother. 2011; 2(1):49-51. PMC: 3117573. DOI: 10.4103/0976-500X.77118. View

Beard Jr R, Haines R, Wu K, Reynolds J, Davis S, Elliott J . Non-muscle Mlck is required for β-catenin- and FoxO1-dependent downregulation of Cldn5 in IL-1β-mediated barrier dysfunction in brain endothelial cells. J Cell Sci. 2014; 127(Pt 8):1840-53. PMC: 4074294. DOI: 10.1242/jcs.144550. View

Adderley S, Zhang X, Breslin J . Involvement of the H1 Histamine Receptor, p38 MAP Kinase, Myosin Light Chains Kinase, and Rho/ROCK in Histamine-Induced Endothelial Barrier Dysfunction. Microcirculation. 2015; 22(4):237-48. PMC: 4412777. DOI: 10.1111/micc.12189. View

Rubin L, Staddon J . The cell biology of the blood-brain barrier. Annu Rev Neurosci. 1999; 22:11-28. DOI: 10.1146/annurev.neuro.22.1.11. View

10.

Breslin J, Sun H, Xu W, Rodarte C, Moy A, Wu M . Involvement of ROCK-mediated endothelial tension development in neutrophil-stimulated microvascular leakage. Am J Physiol Heart Circ Physiol. 2005; 290(2):H741-50. PMC: 2802275. DOI: 10.1152/ajpheart.00238.2005. View

11.

Hawkins B, Davis T . The blood-brain barrier/neurovascular unit in health and disease. Pharmacol Rev. 2005; 57(2):173-85. DOI: 10.1124/pr.57.2.4. View

12.

Doggett T, Alves N, Yuan S, Breslin J . Sphingosine-1-Phosphate Treatment Can Ameliorate Microvascular Leakage Caused by Combined Alcohol Intoxication and Hemorrhagic Shock. Sci Rep. 2017; 7(1):4078. PMC: 5481382. DOI: 10.1038/s41598-017-04157-y. View

13.

Breslin J, Zhang X, Worthylake R, Souza-Smith F . Involvement of local lamellipodia in endothelial barrier function. PLoS One. 2015; 10(2):e0117970. PMC: 4320108. DOI: 10.1371/journal.pone.0117970. View

14.

Sirotkin H, Morrow B, Puech A, Das Gupta R, Patanjali S, Skoultchi A . Identification, characterization, and precise mapping of a human gene encoding a novel membrane-spanning protein from the 22q11 region deleted in velo-cardio-facial syndrome. Genomics. 1997; 42(2):245-51. DOI: 10.1006/geno.1997.4734. View

15.

Singleton P, Dudek S, Ma S, Garcia J . Transactivation of sphingosine 1-phosphate receptors is essential for vascular barrier regulation. Novel role for hyaluronan and CD44 receptor family. J Biol Chem. 2006; 281(45):34381-93. DOI: 10.1074/jbc.M603680200. View

16.

Zhang L, Zeng M, Fan J, Tarbell J, Curry F, Fu B . Sphingosine-1-phosphate Maintains Normal Vascular Permeability by Preserving Endothelial Surface Glycocalyx in Intact Microvessels. Microcirculation. 2016; 23(4):301-10. PMC: 4866498. DOI: 10.1111/micc.12278. View

17.

Kemler R . From cadherins to catenins: cytoplasmic protein interactions and regulation of cell adhesion. Trends Genet. 1993; 9(9):317-21. DOI: 10.1016/0168-9525(93)90250-l. View

18.

Habgood M, Begley D, Abbott N . Determinants of passive drug entry into the central nervous system. Cell Mol Neurobiol. 2000; 20(2):231-53. PMC: 11537553. DOI: 10.1023/a:1007001923498. View

19.

Li Q, Chen B, Zeng C, Fan A, Yuan Y, Guo X . Differential activation of receptors and signal pathways upon stimulation by different doses of sphingosine-1-phosphate in endothelial cells. Exp Physiol. 2015; 100(1):95-107. DOI: 10.1113/expphysiol.2014.082149. View

20.

Zhang X, Adderley S, Breslin J . Activation of RhoA, but Not Rac1, Mediates Early Stages of S1P-Induced Endothelial Barrier Enhancement. PLoS One. 2016; 11(5):e0155490. PMC: 4871357. DOI: 10.1371/journal.pone.0155490. View