Increased production of vascular endothelial growth factor-D and lymphangiogenesis in acute kawasaki disease

Abstract

Background: Kawasaki disease (KD) is characterized by systemic vasculitis with tissue edema. During the healing process of inflammation, lymphangiogenesis is essential for reducing tissue edema. One potential responsible candidate for the induction of lymphangiogenesis in the healing process of acute KD is vascular endothelial growth factor-D (VEGF-D). Methods and Results: Sequential changes in serum VEGF-D levels in patients with acute KD (n=47) using an enzyme-linked immunosorbent assay were investigated. Cross-sectional areas of lymphatic vessels and VEGF-D protein expression were evaluated immunohistochemically in cardiac tissues of patients (n=6) who died of KD. Regulation of VEGF-D messenger RNA (mRNA) expression in cultured fibroblasts was assessed using quantitative real-time polymerase chain reaction. Serum VEGF-D levels increased after intravenous immunoglobulin therapy in patients with acute KD (P<0.001). In addition, they were significantly lower in patients with coronary artery lesions (CAL) than in those without CAL (P<0.05). The cross-sectional areas of lymphatic vessels in cardiac tissues were enlarged in patients with acute KD. VEGF-D protein was detected on the endothelium of the enlarged lymphatic vessels. In vitro, tumor necrosis factor-α significantly down-regulated VEGF-D mRNA expression in cultured fibroblasts (P=0.004). Conclusions: This study indicates that the production of VEGF-D increases and is related to lymphangiogenesis in patients with acute KD. In addition, low VEGF-D production appears to be associated with the development of CAL.