Endothelial progenitor cells induce transplant arteriosclerosis via VEGFR-1/2 activity

Acute rejection (AR) after organ transplantation results in transplant arteriosclerosis (TA). Endothelial progenitor cells (EPCs) are involved in tissue repair and blood vessel formation but are suspected to be a cause of TA.

In this study, we introduced a syngeneic and allogeneic abdominal aortic transplant model with C57BL/6 and BALB/c mice. Syngeneic and allogeneic grafts were histopathologically analyzed after transplantation. Bone marrow-derived EPCs were injected into transplant model animals to observe their distribution and temporal concentration changes. Changes of vascular endothelial growth factor receptor 1 (VEGFR-1), phosphorylated VEGFR-1 (pVEGFR-1), VEGFR-2, pVEGFR-2, protein kinase B (Akt), pAkt, extracellular signal-regulated kinase 1 (Erk1), pErk1 levels in EPCs upon VEGF165 and the VEGFR inhibitor Vandetanib exposure were analyzed in vitro with western blotting.

In the allogeneic transplant group, two weeks after transplantation, formations of new intima layers could be observed, and its proliferation gradually increased to four and six weeks post-transplantation (p < 0.05), accompanied by significant arterial stenoses. Exogenous EPCs mainly localized to the damaged sites of the transplant arteries. In vivo, Vandetanib caused a significant dose dependent decrease of transplant hyperplasia (p < 0.05) and inhibited VEGF related proliferation, migration and adhesion of EPCs.

Vandetanib treatment can reduce arteriosclerosis induced by abdominal aorta transplantation by blocking VEGFRs in EPCs.