title: Vav Guanine nucleotide exchange factors regulate atherosclerotic lesion development in mice.
abstract: OBJECTIVE
  Atherosclerosis requires migration of monocytes to the arterial intima, with subsequent differentiation into foam cells. We showed previously that the scavenger receptor CD36 contributes to the activation of Vav family guanine nucleotide exchange factors (Vavs) in aortae from hyperlipidemic apoE-null mice and that oxidatively modified low-density lipoprotein induced CD36-dependent activation of macrophage Vavs in vitro. We also discovered that CD36-dependent uptake of oxidized low-density lipoprotein and foam cell formation were reduced in Vav-deficient macrophages. We now tested the hypothesis that Vavs play a role in atherosclerotic lesion development.
  
  
  RESULTS
  We showed that apoE/vav1 double-null mice fed a Western diet had significant reduction in total aortic lesion area (by en face analysis) compared with apoE-null mice, with no significant differences in body weight or plasma lipid profiles. Histological analysis of aortic sinus lesions showed fewer macrophages and foam cells in double-null mice compared with apoE-null mice, indicating impaired foam cell generation and homing of macrophages to atherosclerotic lesions. An intravital video microscopy-based adhesion assay with fluorescent (Qtracker655)-labeled monocytes showed reduced adhesion of vav1-null monocytes to hyperlipidemic carotid arteries compared with wild-type monocytes. Furthermore, fewer fluorescently labeled vav1-null monocytes accumulated in aortic sinus lesions in hyperlipidemic apoE-null mice. We also found that activation of RhoGTPase Rac and mitogen-activated protein kinase c-Jun N-terminal kinase-2 by CD36-specific oxidized phospholipids was dependent on Vavs.
  
  
  CONCLUSIONS
  These results for the first time link Vavs to atherosclerotic lesion development and suggest that Vavs act as critical molecular links coupling hyperlipidemia with proatherogenic monocyte/macrophage responses.
authors.affiliation: Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA. rahamao@ccf.org
authors.forename: Shaik O
authors.initials: SO
authors.lastname: Rahaman
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Roy L
authors.initials: RL
authors.lastname: Silverstein
mesh_terms: D000818:Animals; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D018955:CD36 Antigens / Q000378:metabolism; D002340:Carotid Artery Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D002448:Cell Adhesion; D002633:Chemotaxis; D004195:Disease Models, Animal; D005260:Female; D005487:Foam Cells / Q000378:metabolism; D006949:Hyperlipidemias / Q000150:complications / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D018715:Microscopy, Video; D009000:Monocytes / Q000378:metabolism; D058226:Plaque, Atherosclerotic; D051567:Proto-Oncogene Proteins c-vav / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D020744:rac GTP-Binding Proteins / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D018955:CD36 Antigens; D008077:Lipoproteins, LDL; D051567:Proto-Oncogene Proteins c-vav; C496619:Vav1 protein, mouse; C099252:oxidized low density lipoprotein; D048031:JNK Mitogen-Activated Protein Kinases; D020744:rac GTP-Binding Proteins
keywords: CD36; Vav family guanine nucleotide exchange factors; atherosclerosis; foam cells; macrophages