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 language | English |
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Pages (from-to) | e55202 |
Journal | PLOS ONE |
Volume | 8 |
Issue number | 1 |
DOIs | |
Publication status | Published - 2013 |
Keywords
- 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