title: Venous identity is lost but arterial identity is not gained during vein graft adaptation.
abstract: OBJECTIVE
  Ephrin ligands and Eph receptors are signaling molecules that are differentially expressed on arteries and veins during development. We examined whether Eph-B4, a venous marker, and Ephrin-B2, an arterial marker, are regulated during vein graft adaptation in humans and aged rats.
  
  
  RESULTS
  Eph-B4 transcripts and immunodetectable protein are downregulated in endothelial and smooth muscle cells of patent vein grafts in both humans and in aged rats, whereas Ephrin-B2 transcripts and protein are not strongly induced. Other markers of arterial identity, including dll4 and notch-4, are also not induced during vein graft adaptation in aged rats. Because VEGF-A is upstream of the Ephrin-Eph pathway, and expression of VEGF-A is induced only at early time points after exposure of the vein to the arterial environment, we inhibited VEGF-A in vein grafts using an siRNA-based approach. Vein grafts treated with siRNA directed against VEGF-A demonstrated a thicker intima-media containing alpha-actin, consistent with arterialization, but did not contain Eph-B4 or Ephrin-B2.
  
  
  CONCLUSIONS
  Venous identity is preserved in the veins of aged animals, but is lost during adaptation to the arterial circulation; arterial markers are not induced. Markers of vessel identity are plastic in adults and their selective regulation may mediate vein graft adaptation to the arterial environment in aged animals and humans.
authors.affiliation: Yale University School of Medicine, Department of Surgery, New Haven, CT 06519, USA.
authors.forename: Fabio A
authors.initials: FA
authors.lastname: Kudo
authors.forename: Akihito
authors.initials: A
authors.lastname: Muto
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Maloney
authors.forename: Jose M
authors.initials: JM
authors.lastname: Pimiento
authors.forename: Sonia
authors.initials: S
authors.lastname: Bergaya
authors.forename: Tamara N
authors.initials: TN
authors.lastname: Fitzgerald
authors.forename: Tormod S
authors.initials: TS
authors.lastname: Westvik
authors.forename: Jared C
authors.initials: JC
authors.lastname: Frattini
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Breuer
authors.forename: Charles H
authors.initials: CH
authors.lastname: Cha
authors.forename: Toshiya
authors.initials: T
authors.lastname: Nishibe
authors.forename: George
authors.initials: G
authors.lastname: Tellides
authors.forename: William C
authors.initials: WC
authors.lastname: Sessa
authors.forename: Alan
authors.initials: A
authors.lastname: Dardik
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology*; D000367:Age Factors; D000714:Anastomosis, Surgical; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D002339:Carotid Arteries / Q000473:pathology / Q000637:transplantation*; D004195:Disease Models, Animal; D036388:Ephrin-B2 / Q000032:analysis / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018919:Neovascularization, Physiologic; D011336:Probability; D051381:Rats; D011916:Rats, Inbred F344; D036122:Receptor, EphA4 / Q000032:analysis / Q000378:metabolism*; D012307:Risk Factors; D012501:Saphenous Vein / Q000473:pathology / Q000637:transplantation*; D012680:Sensitivity and Specificity; D014656:Vascular Surgical Procedures / Q000379:methods
chemical_list: D015415:Biomarkers; D036388:Ephrin-B2; D036122:Receptor, EphA4