Interleukin‐1α (IL‐1α) promotes angiogenesis in vivo via VEGFR‐2 pathway by inducing inflammatory cell VEGF synthesis and secretion

During inflammation, functional changes occur in the vasculature, including extensive endothelial cell mitotic activity and remodeling of capillaries. Interleukin-1alpha (IL-1alpha)is a prototypical proinflammatory cytokine. Vascular endothelial growth factor (VEGF) is a strong endothelial cell-specific mitogen that exerts a pivotal role in angiogenesis under physiological and pathological conditions. We show that IL-1alpha stimulates VEGF secretion by human peripheral blood mononuclear cells (PBMNCs) in a dose-dependent manner. This represents induction of de novo VEGF synthesis, as an induction of VEGF mRNA was observed. Also, the release of VEGF was blocked by cycloheximide. Reverse transcription-polymerase chain reaction (RT-PCR) detected four VEGF splice variants in unstimulated and in IL-1alpha-stimulated PBMNCs. In vivo in mice, subcutaneously administered IL-1alpha caused a strong local angiogenic response, which was accompanied by an infiltrate of VEGF-expressing inflammatory cells. The angiogenic effect of IL-1a was blocked when the mice were treated with VEGF receptor 2 (VEGFR-2) neutralizing antibodies. VEGFR-1 blocking antibodies had a marginal inhibitory effect on IL-1alpha-induced angiogenesis. These observations indicate that IL-1alpha induces angiogenesis by activating the VEGF-VEGFR-2 signaling pathway between inflammatory cells and blood vessel endothelial cells. This novel mechanism of IL-1alpha-action may enhance the shift to angiogenic phenotype in various conditions designated by excessive angiogenesis.