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

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

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

• Authors: Zhaohua Yang, Can Wang, Shouguo Yang, Tao Hong, Fangshun Wang, Limin Xia, Chunsheng Wang
• Journal: Atherosclerosis (Atherosclerosis) Vol. 238 Issue 1 Pg. 26-32 (Jan 2015) ISSN: 1879-1484 [Electronic] Ireland
• PMID: 25437886 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Piperidines
• Quinazolines
• Vascular Endothelial Growth Factor A
• vascular endothelial growth factor A, mouse
• Vascular Endothelial Growth Factor Receptor-1
• Vascular Endothelial Growth Factor Receptor-2
• vandetanib

Topics

• Animals
• Aorta (transplantation)
• Arteriosclerosis (physiopathology)
• Bone Marrow Cells (cytology)
• Endothelial Cells (cytology)
• Flow Cytometry
• Graft Rejection
• Graft Survival
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Phosphorylation
• Piperidines (chemistry)
• Quinazolines (chemistry)
• Signal Transduction
• Stem Cells (cytology)
• Transplantation, Homologous
• Vascular Endothelial Growth Factor A (metabolism)
• Vascular Endothelial Growth Factor Receptor-1 (metabolism)
• Vascular Endothelial Growth Factor Receptor-2 (metabolism)