Roles of bradykinin in vascular permeability and angiogenesis in solid tumor.

Bradykinin (BK) is involved in tumor angiogenesis. To elucidate the mechanism underlying BK-induced angiogenesis, we evaluated the roles of BK in tumor-associated vascular permeability and angiogenesis in the different phases of tumor development in mice bearing sarcoma 180 cells. The vascular permeability was significantly enhanced in the early growth phase (which peaked at day 5), and was thereafter markedly reduced. By contrast, tumor angiogenesis increased gradually over a 20-day experimental period. Oral administration of a B2 receptor antagonist, FR173657 (30 mg/kg/day), significantly suppressed the vascular permeability, but a B1 antagonist, desArg10-Hoe140 (1 mg/kg/day) did not. An immunohistochemical study revealed the presence of immunoreactive B2 receptor in the endothelial cells in the early phase, whereas B2 receptors were also observed in the stromal fibroblasts in the late phase. We also found that VEGF was detected exclusively in the stromal fibroblasts only in the late phase. Furthermore, VEGF immunoreactivity was attenuated by the treatment with FR173657. Tumor angiogenesis was significantly reduced by treating the tumor tissues with FR173657 both in the early phase (days 1-6, 30 mg/kg/day, oral administration) and in the late phase (days 7-12, 30 mg/kg/day, oral administration), whereas it was inhibited by neutralization with anti-VEGF antibody (1 microg/site/day, local injection) only in the late phase. These results suggest that BK would promote angiogenesis by increasing vascular permeability in the early phase via B2 receptor in the endothelial cells and by promoting up-regulation of VEGF via B2 receptor in the stromal fibroblasts in the late phase.