Objective: To investigate the regulatory effect of EphB4 in the process of vein graft adaptation to arterial blood flow and the mechanism.
Methods: The animal model of artery reconstruction with vein graft was established by transplantation of the superior vena cava of a donor rat to the abdominal aorta of a recipient rat with an end-to-end pattern. The experiment was divided into simple model group (wild type rats were used for both donors and recipients), EphB4 enhancing group (wild type rats were used for both donors and recipients, and the adventitia of the vein graft was continuously stimulated by the EphB4 ligand ephrinB2) and EphB4 lessening group (EphB4+/– transgenic rats were used for donors and wild type rat were used for recipients). The vein grafts in each group of rats were removed for histopathological examinations at 1 week and 4 weeks after model creation. The vein endothelial cells were isolated from wild type and EphB4+/– type rats and cultured, and then, the degrees of phosphorylation of the EphB4 membrane receptor (EphBR) and ERK1/2 in the downstream transduction pathway as well as the migration abilities in the two types of cells were compared.
Results: Compared with the normal rat superior vena cava, the intima-media thickness, and the contents of smooth muscle actin and collagen fiber in the vein grafts of each experimental group of rats were significantly and increasingly elevated (all P<0.05). The increasing amplitudes of all above variables showed no significant difference among the experimental groups at 1 week after model creation (P>0.05), but were significantly less in EphB4 enhancing group than those in the other two groups at 4 weeks after model creation (all P<0.05). Under the stimulation of same concentration of ephrinB2, the degrees of phosphorylation of EphBR and ERK1/2, transcriptional activity of EphB4 mRNA and migration ability in vein the endothelial cells from the EphB4+/–type rats were significantly reduced compared with those from the wild type rats (all P<0.05).
Conclusion: The expression level of the molecular fingerprint EphB4 may play a key role in the remodeling pattern of the vein grafts, and the mechanism is probably associated with its influencing the function of the endothelial cells via ERK1/2 pathway.