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PMID: 19319146 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Transforming growth factor-beta signaling alters substrate permeability and tight junction protein expression at the blood-brain barrier during inflammatory pain.

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism ·Vol. 29 ·No. 6 ·2009-06-00 ·Pages 1084-98

Ronaldson PT, Demarco KM, Sanchez-Covarrubias L, Solinsky CM, Davis TP

Abstract

Our laboratory has shown that peripheral inflammatory pain induced by lambda-carrageenan (CIP) can increase blood-brain barrier (BBB) permeability and alter tight junction (TJ) protein expression leading to changes in BBB functional integrity. However, the intracellular signaling mechanisms involved in this pathophysiologic response have not been elucidated. Transforming growth factor (TGF)-beta signaling pathways are known to regulate vascular integrity and permeability. Therefore, we examined the function of TGF-beta signaling at the BBB in rats subjected to CIP. During CIP, serum TGF-beta1 and protein expression of the TGF-beta receptor activin receptor-like kinase-5 (ALK5) were reduced. Brain permeability to (14)C-sucrose was increased and expression of TJ proteins (i.e., claudin-5, occludin, zonula occluden (ZO-1)) were also altered after 3 h CIP. Pharmacological inhibition of ALK5 with the selective inhibitor SB431542 further enhanced brain uptake of (14)C-sucrose, increased TJ protein expression (i.e., claudin-3, claudin-5, occludin, ZO-1), and decreased nuclear expression of TGF-beta/ALK5 signaling molecules (i.e., Smad2, Smad3), which suggests a role for TGF-beta/ALK5 signaling in the regulation of BBB integrity. Interestingly, administration of exogenous TGF-beta1 before CIP activated the TGF-beta/ALK5 pathway and reduced BBB permeability to (14)C-sucrose. Taken together, our data show that TGF-beta/ALK5 signaling is, in part, involved in the regulation of BBB functional integrity.

MeSH Terms
Activin Receptors/metabolism Animals Blood-Brain Barrier/metabolism Brain/blood supply,drug effects,enzymology Carrageenan/pharmacology Edema/chemically induced,metabolism Female Hot Temperature Humans Inflammation/chemically induced,complications,metabolism Pain/etiology,metabolism Phosphorylation Protein Serine-Threonine Kinases Rats Rats, Sprague-Dawley Receptor, Transforming Growth Factor-beta Type I Receptors, Transforming Growth Factor beta Signal Transduction Smad Proteins/metabolism Substrate Specificity Sucrose/metabolism Tight Junctions/metabolism Transforming Growth Factor beta1/metabolism
Chemicals
Acvrl1 protein, rat Receptors, Transforming Growth Factor beta Smad Proteins Transforming Growth Factor beta1 Sucrose Carrageenan Protein Serine-Threonine Kinases Activin Receptors Receptor, Transforming Growth Factor-beta Type I TGFBR1 protein, human Tgfbr1 protein, rat
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Ronaldson Patrick T
Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona, USA. pronald@email.arizona.edu
Demarco Kristin M
Sanchez-Covarrubias Lucy
Solinsky Christine M
Davis Thomas P
References (41)
41 references, click to expand
  1. TGF-beta receptor kinase inhibitor enhances growth and integrity of embryonic stem cell-derived endothelial cells.
    J Cell Biol. 2003 Dec 22;163(6):1303-11 PMID: 14676305
  2. Arterial endothelium-specific activin receptor-like kinase 1 expression suggests its role in arterialization and vascular remodeling.
    Circ Res. 2003 Oct 3;93(7):682-9 PMID: 12970115
  3. Chronic inflammatory pain leads to increased blood-brain barrier permeability and tight junction protein alterations.
    Am J Physiol Heart Circ Physiol. 2005 Aug;289(2):H738-43 PMID: 15792985
  4. Nociceptive inhibition prevents inflammatory pain induced changes in the blood-brain barrier.
    Brain Res. 2008 Jul 24;1221:6-13 PMID: 18554577
  5. ZO-3, a novel member of the MAGUK protein family found at the tight junction, interacts with ZO-1 and occludin.
    J Cell Biol. 1998 Apr 6;141(1):199-208 PMID: 9531559
  6. Redistribution and phosphorylation of occludin during opening and resealing of tight junctions in cultured epithelial cells.
    J Membr Biol. 1999 Jul 15;170(2):147-56 PMID: 10430658
  7. The human brain GLUT1 glucose transporter: ultrastructural localization to the blood-brain barrier endothelia.
    J Cereb Blood Flow Metab. 1994 Jan;14(1):106-12 PMID: 8263045
  8. The "plantar test" apparatus (Ugo Basile Biological Apparatus), a controlled infrared noxious radiant heat stimulus for precise withdrawal latency measurement in the rat, as a tool for humans?
    Somatosens Mot Res. 1996;13(3-4):215-23 PMID: 9110424
  9. Quantification of early blood-brain barrier disruption by in situ brain perfusion technique.
    Brain Res Brain Res Protoc. 2001 Oct;8(2):126-31 PMID: 11673094
  10. Direct binding of three tight junction-associated MAGUKs, ZO-1, ZO-2, and ZO-3, with the COOH termini of claudins.
    J Cell Biol. 1999 Dec 13;147(6):1351-63 PMID: 10601346
  11. Inflammatory pain alters blood-brain barrier permeability and tight junctional protein expression.
    Am J Physiol Heart Circ Physiol. 2001 Mar;280(3):H1241-8 PMID: 11179069
  12. The blood-brain barrier/neurovascular unit in health and disease.
    Pharmacol Rev. 2005 Jun;57(2):173-85 PMID: 15914466
  13. Dynamics of CNS barriers: evolution, differentiation, and modulation.
    Cell Mol Neurobiol. 2005 Feb;25(1):5-23 PMID: 15962506
  14. Smad-dependent and Smad-independent pathways in TGF-beta family signalling.
    Nature. 2003 Oct 9;425(6958):577-84 PMID: 14534577
  15. Claudin 5 is transiently expressed during the development of the retinal pigment epithelium.
    J Membr Biol. 2002 Mar 15;186(2):81-8 PMID: 11944085
  16. Role of claudin interactions in airway tight junctional permeability.
    Am J Physiol Lung Cell Mol Physiol. 2003 Nov;285(5):L1166-78 PMID: 12909588
  17. Blood outgrowth endothelial cells from Hereditary Haemorrhagic Telangiectasia patients reveal abnormalities compatible with vascular lesions.
    Cardiovasc Res. 2005 Nov 1;68(2):235-48 PMID: 15993872
  18. Astrocytes induce blood-brain barrier properties in endothelial cells.
    Nature. 1987 Jan 15-21;325(6101):253-7 PMID: 3543687
  19. Up-regulation of P-glycoprotein by HIV protease inhibitors in a human brain microvessel endothelial cell line.
    J Neurosci Res. 2009 Mar;87(4):1023-36 PMID: 18855943
  20. Expression of transforming growth factor-beta1, 2, 3 isoforms and type I and II receptors in acute focal cerebral ischemia: an immunohistochemical study in rat after transient and permanent occlusion of middle cerebral artery.
    Acta Neuropathol. 1999 May;97(5):447-55 PMID: 10334481
  21. Distinct regulation of gene expression in human endothelial cells by TGF-beta and its receptors.
    Microvasc Res. 2006 Jan;71(1):12-9 PMID: 16405919
  22. Transforming growth factor-beta1 upregulates the tight junction and P-glycoprotein of brain microvascular endothelial cells.
    Cell Mol Neurobiol. 2004 Jun;24(3):491-7 PMID: 15206827
  23. Abnormal angiogenesis but intact hematopoietic potential in TGF-beta type I receptor-deficient mice.
    EMBO J. 2001 Apr 2;20(7):1663-73 PMID: 11285230
  24. Alterations in blood-brain barrier ICAM-1 expression and brain microglial activation after lambda-carrageenan-induced inflammatory pain.
    Am J Physiol Heart Circ Physiol. 2006 Feb;290(2):H732-40 PMID: 16199477
  25. Defective haematopoiesis and vasculogenesis in transforming growth factor-beta 1 knock out mice.
    Development. 1995 Jun;121(6):1845-54 PMID: 7600998
  26. Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors.
    EMBO J. 2002 Apr 2;21(7):1743-53 PMID: 11927558
  27. Protein kinase C regulates the phosphorylation and cellular localization of occludin.
    J Biol Chem. 2001 Oct 19;276(42):38480-6 PMID: 11502742
  28. Occludin oligomeric assembly at tight junctions of the blood-brain barrier is disrupted by peripheral inflammatory hyperalgesia.
    J Neurochem. 2008 Sep;106(6):2395-409 PMID: 18647175
  29. Phosphorylation of cAMP responsive element binding protein after treatment of mesangial cells with high glucose plus TGF beta or PMA.
    Kidney Int. 1996 Sep;50(3):805-10 PMID: 8872954
  30. Expression of transforming growth factor (TGF)-beta1, -beta2, and -beta3 isoforms and TGF-beta type I and type II receptors in multiple sclerosis lesions and human adult astrocyte cultures.
    J Neuropathol Exp Neurol. 1999 Feb;58(2):174-87 PMID: 10029100
  31. Endothelial cell barrier impairment induced by glioblastomas and transforming growth factor beta2 involves matrix metalloproteinases and tight junction proteins.
    J Neuropathol Exp Neurol. 2008 May;67(5):435-48 PMID: 18431253
  32. ALK5 and Smad4 are involved in TGF-beta1-induced pulmonary endothelial permeability.
    FEBS Lett. 2005 Jul 18;579(18):4031-7 PMID: 16004987
  33. Transforming growth factor-beta: vasculogenesis, angiogenesis, and vessel wall integrity.
    Cytokine Growth Factor Rev. 1997 Mar;8(1):21-43 PMID: 9174661
  34. SB-431542 is a potent and specific inhibitor of transforming growth factor-beta superfamily type I activin receptor-like kinase (ALK) receptors ALK4, ALK5, and ALK7.
    Mol Pharmacol. 2002 Jul;62(1):65-74 PMID: 12065756
  35. Vascular endothelial growth factor induces rapid phosphorylation of tight junction proteins occludin and zonula occluden 1. A potential mechanism for vascular permeability in diabetic retinopathy and tumors.
    J Biol Chem. 1999 Aug 13;274(33):23463-7 PMID: 10438525
  36. Electrical resistance across the blood-brain barrier in anaesthetized rats: a developmental study.
    J Physiol. 1990 Oct;429:47-62 PMID: 2277354
  37. Inhibition of transforming growth factor (TGF)-beta1-induced extracellular matrix with a novel inhibitor of the TGF-beta type I receptor kinase activity: SB-431542.
    Mol Pharmacol. 2002 Jul;62(1):58-64 PMID: 12065755
  38. Blood-brain barrier tight junctions are altered during a 72-h exposure to lambda-carrageenan-induced inflammatory pain.
    Am J Physiol Heart Circ Physiol. 2002 Oct;283(4):H1531-7 PMID: 12234806
  39. Activin receptor-like kinase 1 modulates transforming growth factor-beta 1 signaling in the regulation of angiogenesis.
    Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2626-31 PMID: 10716993
  40. TGF-beta receptor function in the endothelium.
    Cardiovasc Res. 2005 Feb 15;65(3):599-608 PMID: 15664386
  41. Endoglin promotes endothelial cell proliferation and TGF-beta/ALK1 signal transduction.
    EMBO J. 2004 Oct 13;23(20):4018-28 PMID: 15385967
Article Info
Journal
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
Abbr.
J Cereb Blood Flow Metab
ISSN
1559-7016
DOI
10.1038/jcbfm.2009.32
Email
pronald@email.arizona.edu
Published
2009-06-00
Epub
2009-00-25
Pages
1084-98
Language
English
Region
United States
NLM ID
8112566
PMCID
PMC3910515
Subset
IM
Grants
NIDA NIH HHS · R01 DA011271 · United States
NINDS NIH HHS · R01 NS042652 · United States
NIDA NIH HHS · R01-DA11271 · United States
NINDS NIH HHS · R01-NS42652 · United States
External Links
PubMed source DOI: 10.1038/jcbfm.2009.32 PMC Full Text View journal details
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