Inhibition of vascular endothelial growth factor reduces cardiac allograft vasculopathy

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• 作者：Safia Chatur ; BSc ; MD ; Brian W-C Wong ; BMLSc ; PhD ; Jon M. Carthy ; BSc ; PhD ; Bruce M. McManus ; PhD ; MDup> ; up>up>elishah.velji@hli.ubc.ca" class="auth_mail" title="E-mail the corresponding authorup>
• 关键词：cardiac allograft vasculopathy ; murine heterotopic model ; VEGF inhibition ; vascular outgrowth
• 刊名：Journal of Heart and Lung Transplantation
• 出版年：2016
• 出版时间：September 2016
• 年：2016
• 卷：35
• 期：9
• 页码：1124-1130
• 全文大小：1543 K

文摘

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.