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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1562.)
© 2007 American Heart Association, Inc.

Vascular Biology

Venous Identity Is Lost but Arterial Identity Is Not Gained During Vein Graft Adaptation

Fabio A. Kudo; Akihito Muto; Stephen P. Maloney; Jose M. Pimiento; Sonia Bergaya; Tamara N. Fitzgerald; Tormod S. Westvik; Jared C. Frattini; Christopher K. Breuer; Charles H. Cha; Toshiya Nishibe; George Tellides; William C. Sessa; Alan Dardik

From the Departments of Surgery (F.A.K., A.M., S.P.M., J.M.P., T.N.F., T.S.W., J.C.F., C.K.B., C.H.C., G.T., A.D.) and Pharmacology (S.B., W.C.S.) and the Interdepartmental Program in Vascular Biology and Transplantation (C.K.B., G.T., W.C.S., A.D.), Yale University School of Medicine, New Haven, Conn; the VA Connecticut Healthcare System (C.H.C., G.T., A.D.), West Haven, Conn; and the Fujita Health University (T.N.), Nagoya, Japan.

Correspondence to Alan Dardik, MD, PhD, Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Ave, Room 436, New Haven, CT 06519. E-mail alan.dardik{at}yale.edu

Objectives— 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.

Methods and 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 -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.

In human and aged rat vein graft adaptation, Eph-B4, a marker of venous identity, is downregulated, whereas markers of arterial identity such as Ephrin-B2 are not induced. These results suggest that markers of vessel identity that are developmentally regulated are plastic in adults.

Key Words: vein graft adaptation • venous identity • Eph-B4 • Ephrin-B2 • remodeling • smooth muscle cells

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