Identification of an essential endogenous regulator of blood-brain barrier integrity, and its pathological and therapeutic implications

Proc Natl Acad Sci U S A. 2013 Jan 15;110(3):832-41. doi: 10.1073/pnas.1209362110. Epub 2012 Dec 31.


The blood-brain barrier (BBB), a critical guardian of communication between the periphery and the brain, is frequently compromised in neurological diseases such as multiple sclerosis (MS), resulting in the inappropriate passage of molecules and leukocytes into the brain. Here we show that the glucocorticoid anti-inflammatory messenger annexin A1 (ANXA1) is expressed in brain microvascular endothelial cells, where it regulates BBB integrity. In particular, ANXA1(-/-) mice exhibit significantly increased BBB permeability as a result of disrupted interendothelial cell tight junctions, essentially related to changes in the actin cytoskeleton, which stabilizes tight and adherens junctions. This situation is reminiscent of early MS pathology, a relationship confirmed by our detection of a selective loss of ANXA1 in the plasma and cerebrovascular endothelium of patients with MS. Importantly, this loss is swiftly restored by i.v. administration of human recombinant ANXA1. Analysis in vitro confirms that treatment of cerebrovascular endothelial cells with recombinant ANXA1 restores cell polarity, cytoskeleton integrity, and paracellular permeability through inhibition of the small G protein RhoA. We thus propose ANXA1 as a critical physiological regulator of BBB integrity and suggest it may have utility in the treatment of MS, correcting BBB function and hence ameliorating disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Cytoskeleton / physiology
  • Adherens Junctions / pathology
  • Adherens Junctions / physiology
  • Adult
  • Aged
  • Animals
  • Annexin A1 / antagonists & inhibitors
  • Annexin A1 / deficiency
  • Annexin A1 / genetics
  • Annexin A1 / pharmacology
  • Annexin A1 / physiology*
  • Blood-Brain Barrier / pathology
  • Blood-Brain Barrier / physiology*
  • Blood-Brain Barrier / physiopathology
  • Capillary Permeability / physiology
  • Cell Line
  • Endothelial Cells / pathology
  • Endothelial Cells / physiology
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microvessels / pathology
  • Microvessels / physiopathology
  • Middle Aged
  • Models, Neurological
  • Multiple Sclerosis / pathology
  • Multiple Sclerosis / physiopathology
  • Recombinant Proteins / genetics
  • Recombinant Proteins / pharmacology
  • Tight Junction Proteins / physiology
  • rhoA GTP-Binding Protein / metabolism


  • Annexin A1
  • Recombinant Proteins
  • Tight Junction Proteins
  • annexin A1, mouse
  • RHOA protein, human
  • rhoA GTP-Binding Protein