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
Samson, Thomas ; van Buul, Jaap D ; Kroon, Jeffrey ; Welch, Christopher ; Bakker, Erik N ; Matlung, Hanke L ; van den Berg, Timo K ; Sharek, Lisa ; Doerschuk, Claire ; Hahn, Klaus ; Burridge, Keith. / The guanine-nucleotide exchange factor SGEF plays a crucial role in the formation of atherosclerosis. In: PLoS ONE. 2013 ; Vol. 8, No. 1. pp. e55202.
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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.",
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Samson, T, van Buul, JD, Kroon, J, Welch, C, Bakker, EN, Matlung, HL, van den Berg, TK, Sharek, L, Doerschuk, C, Hahn, K & Burridge, K 2013, 'The guanine-nucleotide exchange factor SGEF plays a crucial role in the formation of atherosclerosis' PLoS ONE, vol. 8, no. 1, pp. e55202. https://doi.org/10.1371/journal.pone.0055202

The guanine-nucleotide exchange factor SGEF plays a crucial role in the formation of atherosclerosis. / Samson, Thomas; van Buul, Jaap D; Kroon, Jeffrey; Welch, Christopher; Bakker, Erik N; Matlung, Hanke L; van den Berg, Timo K; Sharek, Lisa; Doerschuk, Claire; Hahn, Klaus; Burridge, Keith.

In: PLoS ONE, Vol. 8, No. 1, 2013, p. e55202.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - The guanine-nucleotide exchange factor SGEF plays a crucial role in the formation of atherosclerosis

AU - Samson, Thomas

AU - van Buul, Jaap D

AU - Kroon, Jeffrey

AU - Welch, Christopher

AU - Bakker, Erik N

AU - Matlung, Hanke L

AU - van den Berg, Timo K

AU - Sharek, Lisa

AU - Doerschuk, Claire

AU - Hahn, Klaus

AU - Burridge, Keith

PY - 2013

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N2 - 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.

AB - 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.

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KW - Aorta/metabolism

KW - Apolipoproteins E/deficiency

KW - Atherosclerosis/genetics

KW - Cell Line

KW - Disease Models, Animal

KW - Endothelial Cells/diagnostic imaging

KW - GTP Phosphohydrolases/genetics

KW - Gene Order

KW - Gene Silencing

KW - Gene Targeting

KW - Guanine Nucleotide Exchange Factors/genetics

KW - Humans

KW - Intercellular Adhesion Molecule-1/metabolism

KW - Mice

KW - Mice, Knockout

KW - Phenotype

KW - Ultrasonography

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