The guanine-nucleotide exchange factor SGEF plays a crucial role in the formation of atherosclerosis.
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.
Department of Cell Biology and Physiology, and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
Thomas
T
Samson
Jaap D
JD
van Buul
Jeffrey
J
Kroon
Christopher
C
Welch
Erik N
EN
Bakker
Hanke L
HL
Matlung
Timo K
TK
van den Berg
Lisa
L
Sharek
Claire
C
Doerschuk
Klaus
K
Hahn
Keith
K
Burridge
D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D023061:Gene Order; D020868:Gene Silencing; D018390:Gene Targeting; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D014463:Ultrasonography; D020741:rho GTP-Binding Proteins
D001057:Apolipoproteins E; D020662:Guanine Nucleotide Exchange Factors; C489577:Rhog protein, mouse; C582467:SGEF protein, mouse; D018799:Intercellular Adhesion Molecule-1; D020558:GTP Phosphohydrolases; D020741:rho GTP-Binding Proteins