SSeCKS regulates angiogenesis and tight junction formation in blood-brain barrier

Nat Med. 2003 Jul;9(7):900-6. doi: 10.1038/nm889.


The blood-brain barrier (BBB) is essential for maintaining brain homeostasis and low permeability. BBB maintenance is important in the central nervous system (CNS) because disruption of the BBB may contribute to many brain disorders, including Alzheimer disease and ischemic stroke. The molecular mechanisms of BBB development remain ill-defined, however. Here we report that src-suppressed C-kinase substrate (SSeCKS) decreases the expression of vascular endothelial growth factor (VEGF) through AP-1 reduction and stimulates expression of angiopoietin-1 (Ang-1), an antipermeability factor in astrocytes. Conditioned media from SSeCKS-overexpressing astrocytes (SSeCKS-CM) blocked angiogenesis in vivo and in vitro. Moreover, SSeCKS-CM increased tight junction proteins in endothelial cells, consequently decreasing [3H]sucrose permeability. Furthermore, immunoreactivity to SSeCKS gradually increased during the BBB maturation period, and SSeCKS-expressing astrocytes closely interacted with zonula occludens (ZO)-1-expressing blood vessels in vivo. Collectively, our results suggest that SSeCKS regulates BBB differentiation by modulating both brain angiogenesis and tight junction formation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A Kinase Anchor Proteins
  • Angiogenesis Inducing Agents / metabolism
  • Angiopoietin-1
  • Animals
  • Astrocytes / physiology
  • Blood Vessels / metabolism
  • Blood-Brain Barrier / physiology*
  • Brain / embryology
  • Brain / metabolism
  • Cell Cycle Proteins*
  • Cell Hypoxia
  • Cells, Cultured
  • Endothelial Growth Factors / metabolism
  • Female
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Lymphokines / metabolism
  • Male
  • Membrane Glycoproteins / metabolism
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mitogens / genetics
  • Mitogens / metabolism*
  • Neovascularization, Physiologic / physiology*
  • Oligonucleotide Array Sequence Analysis
  • Permeability
  • Phosphoproteins / metabolism
  • Pregnancy
  • Rats
  • Rats, Sprague-Dawley
  • Sucrose / metabolism
  • Tight Junctions / physiology*
  • Transcription Factor AP-1 / metabolism
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Zonula Occludens-1 Protein


  • A Kinase Anchor Proteins
  • Akap12 protein, mouse
  • Akap12 protein, rat
  • Angiogenesis Inducing Agents
  • Angiopoietin-1
  • Angpt1 protein, mouse
  • Angpt1 protein, rat
  • Cell Cycle Proteins
  • Endothelial Growth Factors
  • Intercellular Signaling Peptides and Proteins
  • Lymphokines
  • Membrane Glycoproteins
  • Membrane Proteins
  • Mitogens
  • Phosphoproteins
  • Tjp1 protein, mouse
  • Tjp1 protein, rat
  • Transcription Factor AP-1
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Zonula Occludens-1 Protein
  • Sucrose