The guanine-nucleotide exchange factor SGEF plays a crucial role in the formation of atherosclerosis

Thomas Samson, Jeffrey Kroon, Christopher Welch, Erik N Bakker, Hanke L Matlung, Timo K van den Berg, Lisa Sharek, Claire Doerschuk, Klaus Hahn, Keith Burridge

Research output: Contribution to journalArticleAcademicpeer-review

25 Citations (Scopus)


The passage of leukocytes across the endothelium and into arterial walls is a critical step in the development of atherosclerosis. Previously, we showed in vitro that the RhoG guanine nucleotide exchange factor SGEF (Arhgef26) contributes to the formation of ICAM-1-induced endothelial docking structures that facilitate leukocyte transendothelial migration. To further explore the in vivo role of this protein during inflammation, we generated SGEF-deficient mice. When crossed with ApoE null mice and fed a Western diet, mice lacking SGEF showed a significant decrease in the formation of atherosclerosis in multiple aortic areas. A fluorescent biosensor revealed local activation of RhoG around bead-clustered ICAM-1 in mouse aortic endothelial cells. Notably, this activation was decreased in cells from SGEF-deficient aortas compared to wild type. In addition, scanning electron microscopy of intimal surfaces of SGEF(-/-) mouse aortas revealed reduced docking structures around beads that were coated with ICAM-1 antibody. Similarly, under conditions of flow, these beads adhered less stably to the luminal surface of carotid arteries from SGEF(-/-) mice. Taken together, these results show for the first time that a Rho-GEF, namely SGEF, contributes to the formation of atherosclerosis by promoting endothelial docking structures and thereby retention of leukocytes at athero-prone sites of inflammation experiencing high shear flow. SGEF may therefore provide a novel therapeutic target for inhibiting the development of atherosclerosis.

Original languageEnglish
Pages (from-to)e55202
Issue number1
Publication statusPublished - 2013


  • Animals
  • Aorta/metabolism
  • Apolipoproteins E/deficiency
  • Atherosclerosis/genetics
  • Cell Line
  • Disease Models, Animal
  • Endothelial Cells/diagnostic imaging
  • GTP Phosphohydrolases/genetics
  • Gene Order
  • Gene Silencing
  • Gene Targeting
  • Guanine Nucleotide Exchange Factors/genetics
  • Humans
  • Intercellular Adhesion Molecule-1/metabolism
  • Mice
  • Mice, Knockout
  • Phenotype
  • Ultrasonography

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