Venous identity is lost but arterial identity is not gained during vein graft adaptation.
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.
Kudo
Fabio A
FA
Yale University School of Medicine, Department of Surgery, New Haven, CT 06519, USA.
Muto
Akihito
A
Maloney
Stephen P
SP
Pimiento
Jose M
JM
Bergaya
Sonia
S
Fitzgerald
Tamara N
TN
Westvik
Tormod S
TS
Frattini
Jared C
JC
Breuer
Christopher K
CK
Cha
Charles H
CH
Nishibe
Toshiya
T
Tellides
George
G
Sessa
William C
WC
Dardik
Alan
A
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
D015415:Biomarkers; D036388:Ephrin-B2; D036122:Receptor, EphA4