Expression patterns of vascular endothelial growth factor in human cardiac allografts: Association with rejection

Background. Vascular endothelial growth factor (VEGF), a major angiogenesis factor, has been found to have proinflammatory properties in vivo in several chronic inflammatory diseases. However, little is known of the expression or function of VEGF in acute and chronic allograft rejection. Methods. In a cross-sectional analysis, we evaluated the expression of VEGF by immunohistochemistry in human endomyocardial biopsies (n=101) from 10 cardiac transplant patients. We correlated expression (scores from 0-4) with CD3⁺ T cell, CD68⁺ monocyte and macrophage infiltrates, or rejection (International Society of Heart and Lung Transplantation grades 0-4). In addition, we evaluated the temporal patterns of VEGF expression in consecutive biopsies from seven patients (total of 74 biopsies) who were assessed for the development of graft vascular disease (GVD) by intravascular ultrasonography at 1 year posttransplantation. Results. VEGF is expressed in normal human endomyocardial biopsies at low levels and is induced (scores > 1) in association with CD3⁺ T cells (odds ratio [OR], 19.90; P<0.001), CD68⁺ monocyte and macrophage infiltrates (OR, 8.49; P<0.001), and all grades of acute rejection (OR, 5.4; P<0.001). Increases in VEGF expression were persistent during the first posttransplant year in biopsies from four patients who demonstrated evidence of GVD (mean annual score of 2.3). In contrast, limited expression of VEGF was found in three patients without GVD (mean annual score 1.2). Conclusions. These findings define VEGF as an important proinflammatory cytokine after transplantation and indicate that its expression pattern might identify patients at risk for the development of GVD.