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Updated: Mar 19, 2026
Murine Cervical Aortic Transplantation Model using a Modified Non-Suture Cuff Technique
Published on: November 2, 2019
Inhibition of vascular endothelial growth factor reduces cardiac allograft vasculopathy
Safia Chatur1, Brian W-C Wong1, Jon M Carthy1
1UBC James Hogg Research Centre, Institute for Heart + Lung Health, Department of Pathology and Laboratory Medicine, University of British Columbia-Providence Health Care, Vancouver, British Columbia, Canada.
Insights
Vascular endothelial growth factor (VEGF) inhibition significantly reduced cardiac allograft vasculopathy (CAV) in mice. This approach may offer a new strategy for preventing and treating CAV by reducing graft neo-angiogenesis and inflammation.
Area of Science:
- Cardiovascular Research
- Transplantation Immunology
- Oncology (VEGF signaling relevance)
Background:
- Cardiac allograft vasculopathy (CAV) is a major cause of chronic rejection after heart transplantation.
- Vascular endothelial growth factor (VEGF) overexpression in allografts is implicated in CAV pathogenesis through graft neo-angiogenesis.
- Host bone marrow-derived cells contribute to CAV development.
Purpose of the Study:
- To investigate the therapeutic effect of inhibiting VEGF expression in a mouse model of CAV.
- To assess the impact of VEGF inhibition on bone marrow-mediated microvascular changes and endothelial cell function.
Main Methods:
- A mouse model of cardiac transplantation was established using heterotopic heart grafts.
- Treatment with soluble VEGF receptor 1 (sVEGFR1) or vehicle control was administered.
- In vitro assays evaluated angiogenesis, endothelial cell migration, and proliferation.
Main Results:
- sVEGFR1 treatment significantly reduced luminal narrowing and the percentage of affected vessels in allografts.
- VEGF inhibition decreased graft weight and attenuated myocardial edema and neo-angiogenesis.
- In vitro, VEGF inhibition suppressed bone marrow-mediated microvascular outgrowth, endothelial cell migration, and proliferation.
Conclusions:
- VEGF inhibition effectively reduces the severity and incidence of CAV in a murine model.
- VEGF signaling plays a critical role in bone marrow-derived cell-mediated microvascular responses contributing to CAV.
- Targeting VEGF may represent a promising therapeutic strategy for CAV prevention and treatment.
Background:
Cardiac allograft vasculopathy (CAV) is a leading expression of chronic organ rejection at and beyond 1 year post-transplantation. Host bone marrow (BM)-derived cell migration to the allograft has been demonstrated in earlier work. Vascular endothelial growth factor (VEGF) is endogenously overexpressed within allografts. Graft neo-angiogenesis has been proposed as a mechanism by which VEGF may contribute to CAV. Herein we assess the therapeutic effect of inhibition of VEGF expression in CAV.
Methods:
In 129J mice, female donor hearts were heterotopically transplanted into C57/B16 males and treated with soluble VEGF receptor 1 (sVEGFR1) or vehicle control. The effect of VEGF inhibition on BM-mediated microvascular outgrowth and endothelial cell migration and proliferation were assessed using in vitro assays of aortic ring angiogenesis, wound healing and proliferation, respectively.
Results:
At 21 days post-transplantation, treatment with sVEGFR1 significantly reduced both percent luminal narrowing (p < 0.05) and percent of vessels affected (p < 0.005). sVEGFR1 significantly reduced average wet heart weight (p < 0.05), whereas mean ventricular cross-sectional area remained similar. Treatment of aortic rings with both sVEGFR1 and VEGFR2 tyrosine phosphorylation inhibitor (Ki 8751) significantly reduced BM-mediated microvascular outgrowth length (p < 0.05) and area (p < 0.05). Treatment of human coronary artery endothelial cells with sVEGFR1 and Ki 8751 significantly reduced BM-mediated endothelial cell migration (p < 0.005) and proliferation (p < 0.05).
Conclusions:
VEGF inhibition reduces the severity and incidence of CAV in mouse models of cardiac transplantation, while attenuating myocardial edema and neo-angiogenesis. Using this model, we provide in vitro evidence of the role of VEGF signaling in BM-mediated microvascular outgrowth and endothelial cell migration and proliferation. VEGF inhibition may represent a novel approach to CAV treatment and prevention.
