Interleukin-1alpha 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.
Division of Hematology-Oncology, Weill Medical College of Cornell University, New York, New York 10021, USA. petri.salven@helsinki.fi
Petri
P
Salven
Koichi
K
Hattori
Beate
B
Heissig
Shahin
S
Rafii
D017398:Alternative Splicing; D000818:Animals; D001808:Blood Vessels / Q000033:anatomy & histology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism*; D008222:Lymphokines / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D018919:Neovascularization, Physiologic; D012333:RNA, Messenger / Q000096:biosynthesis; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D017978:Receptors, Growth Factor / Q000502:physiology*; D040262:Receptors, Vascular Endothelial Growth Factor; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D007375:Interleukin-1; D008222:Lymphokines; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor