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

Thomas Samson, Jaap D van Buul, 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

Abstract

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
JournalPLoS ONE
Volume8
Issue number1
DOIs
Publication statusPublished - 2013

Cite this

Samson, T., van Buul, J. D., Kroon, J., Welch, C., Bakker, E. N., Matlung, H. L., ... Burridge, K. (2013). The guanine-nucleotide exchange factor SGEF plays a crucial role in the formation of atherosclerosis. PLoS ONE, 8(1), e55202. https://doi.org/10.1371/journal.pone.0055202