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

Patrick T. Ronaldson, Kristin M. Demarco, Lucy Sanchez-Covarrubias, Christine M. Solinsky, Thomas P. Davis

Research output: Contribution to journalArticle

88 Scopus citations

Abstract

Our laboratory has shown that peripheral inflammatory pain induced by -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)-Β signaling pathways are known to regulate vascular integrity and permeability. Therefore, we examined the function of TGF-Β signaling at the BBB in rats subjected to CIP. During CIP, serum TGF-Β1 and protein expression of the TGF-Β 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-Β/ALK5 signaling molecules (i.e., Smad2, Smad3), which suggests a role for TGF-Β/ALK5 signaling in the regulation of BBB integrity. Interestingly, administration of exogenous TGF-Β1 before CIP activated the TGF-Β/ALK5 pathway and reduced BBB permeability to 14 C-sucrose. Taken together, our data show that TGF-Β/ALK5 signaling is, in part, involved in the regulation of BBB functional integrity.

Original languageEnglish (US)
Pages (from-to)1084-1098
Number of pages15
JournalJournal of Cerebral Blood Flow and Metabolism
Volume29
Issue number6
DOIs
StatePublished - Jun 2009

Keywords

  • Blood?brain barrier
  • Brain vascular permeability
  • Inflammatory pain
  • Tight junctions
  • Transforming growth factor-b

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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