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 α-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.

Stimulation of Eph-B4 prevents adaptive remodeling and preserves venous identity when veins are surgically placed into an arterial environment.

Patch angioplasty is commonly performed after carotid endarterectomy. Randomized prospective trials and meta-analyses have documented improved rates of perioperative and long-term stroke prevention as well as reduced rates of restenosis for patches compared to primary closure of the arteriotomy. Although use of vein patches is considered to be the “gold standard” for patch closure, newer generations of synthetic and biological materials rival outcomes associated with vein patches. Future bioengineered patches are likely to optimize patch performance, both by achieving minimal stroke risk and long-term rates of restenosis, as well as by minimizing the risk of unusual complications of prosthetic patches such as infection and pseudoaneurysm formation; in addition, lessons from bioengineered patches will likely enable construction of bioengineered and tissue-engineered bypass grafts.