title: EphA2 activation promotes the endothelial cell inflammatory response: a potential role in atherosclerosis.
abstract: OBJECTIVE
  Endothelial cell activation results in altered cell-cell interactions with adjacent endothelial cells and with infiltrating leukocytes. Eph receptors and their ephrin ligands regulate cell-cell interactions during tissue remodeling, and multiple proinflammatory mediators induce endothelial EphA receptor and ephrinA ligand expression. Therefore, we sought to elucidate the role of EphA receptors and ephrinA ligands in endothelial cell activation and atherosclerosis.
  
  
  RESULTS
  Quantitative reverse transcription-polymerase chain reaction screening for EphA/ephrinA expression in atherosclerosis-prone macrovascular endothelium identified EphA2, EphA4, and ephrinA1 as the dominant isoforms. Endothelial activation with oxidized low-density lipoprotein and proinflammatory cytokines induced EphA2 and ephrinA1 expression and sustained EphA2 activation, whereas EphA4 expression was unaffected. Atherosclerotic plaques from mice and humans showed enhanced EphA2 and ephrinA1 expression colocalizing in the endothelial cell layer. EphA2 activation with recombinant Fc-ephrinA1 induced proinflammatory gene expression (eg vascular cell adhesion molecule-1, E-selectin) and stimulated monocyte adhesion, whereas inhibiting EphA2 (small interfering RNA, pharmacological inhibitors) abrogated both ephrinA1-induced and oxidized low-density lipoprotein-induced vascular cell adhesion molecule-1 expression.
  
  
  CONCLUSIONS
  The current data suggest that enhanced EphA2 signaling during endothelial cell activation perpetuates proinflammatory gene expression. Coupled with EphA2 expression in mouse and human atherosclerotic plaques, these data implicate EphA2 as a novel proinflammatory mediator and potential regulator of atherosclerotic plaque development.
authors.affiliation: Department of Pathology, Louisiana State University Health Science Center, 1501 King's Hwy, Shreveport, LA 71130, USA.
authors.forename: Steven Daniel
authors.initials: SD
authors.lastname: Funk
authors.forename: Arif
authors.initials: A
authors.lastname: Yurdagul
authors.forename: Patrick
authors.initials: P
authors.lastname: Albert
authors.forename: James G
authors.initials: JG
authors.lastname: Traylor
authors.forename: Long
authors.initials: L
authors.lastname: Jin
authors.forename: Jin
authors.initials: J
authors.lastname: Chen
authors.forename: A Wayne
authors.initials: AW
authors.lastname: Orr
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002448:Cell Adhesion; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology; D010641:Phenotype; D034622:RNA Interference; D036104:Receptor, EphA2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
chemical_list: D001057:Apolipoproteins E; D016207:Cytokines; D018836:Inflammation Mediators; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D036104:Receptor, EphA2