title: Endothelial expression of guidance cues in vessel wall homeostasis dysregulation under proatherosclerotic conditions.
abstract: OBJECTIVE
  Emerging evidence suggests that neuronal guidance cues, typically expressed during development, are involved in both physiological and pathological immune responses. We hypothesized that endothelial expression of such guidance cues may regulate leukocyte trafficking into the vascular wall during atherogenesis.
  
  
  RESULTS
  We demonstrate that members of the netrin, semaphorin, and ephrin family of guidance molecules are differentially regulated under conditions that promote or protect from atherosclerosis. Netrin-1 and semaphorin3A are expressed by coronary artery endothelial cells and potently inhibit chemokine-directed migration of human monocytes. Endothelial expression of these negative guidance cues is downregulated by proatherogenic factors, including oscillatory shear stress and proinflammatory cytokines associated with monocyte entry into the vessel wall. Furthermore, we show using intravital microscopy that inhibition of netrin-1 or semaphorin3A using blocking peptides increases leukocyte adhesion to the endothelium. Unlike netrin-1 and semaphorin3A, the guidance cue ephrinB2 is upregulated under proatherosclerotic flow conditions and functions as a chemoattractant, increasing leukocyte migration in the absence of additional chemokines.
  
  
  CONCLUSIONS
  The concurrent regulation of negative and positive guidance cues may facilitate leukocyte infiltration of the endothelium through a balance between chemoattraction and chemorepulsion. These data indicate a previously unappreciated role for axonal guidance cues in maintaining the endothelial barrier and regulating leukocyte trafficking during atherogenesis.
authors: Marc and Ruti Bell Vascular Biology and Disease Program, Leon H. Charney Division of Cardiology, Department of Medicine, NewYork University School of Medicine, New York, NY 10016, USA.
authors: Janine M
authors: JM
authors: van Gils
authors: Bhama
authors: B
authors: Ramkhelawon
authors: Luciana
authors: L
authors: Fernandes
authors: Merran C
authors: MC
authors: Stewart
authors: Liang
authors: L
authors: Guo
authors: Tara
authors: T
authors: Seibert
authors: Gustavo B
authors: GB
authors: Menezes
authors: Denise C
authors: DC
authors: Cara
authors: Camille
authors: C
authors: Chow
authors: T Bernard
authors: TB
authors: Kinane
authors: Edward A
authors: EA
authors: Fisher
authors: Mercedes
authors: M
authors: Balcells
authors: Jacqueline
authors: J
authors: Alvarez-Leite
authors: Adam
authors: A
authors: Lacy-Hulbert
authors: Kathryn J
authors: KJ
authors: Moore
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism*; D036388:Ephrin-B2 / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation; D006706:Homeostasis; D006801:Humans; D007962:Leukocytes / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors / Q000235:genetics / Q000502:physiology*; D000075388:Netrin-1; D040121:Semaphorin-3A / Q000235:genetics / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D036388:Ephrin-B2; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; C488217:Sema3a protein, mouse; D040121:Semaphorin-3A; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1