In vivo activation of JAK2/STAT-3 pathway during angiogenesis induced by GM-CSF.
Besides the regulation of hematopoiesis, granulocyte-macrophage colony-stimulating factor (GM-CSF) induces the expression of a functional program in cultured endothelial cells (ECs) related to angiogenesis and to the their survival in bone marrow microenvironment. ECs express the specific GM-CSF receptor that signals through the recruitment and the activation of Janus kinase (JAK)2 (Soldi et al., Blood 89, 863-872, 1987). We now report that GM-CSF in vivo induces angiogenesis and activates JAK-2 and signal transducers and activators of transcription (STAT)-3. This cytokine has an angiogenetic activity in chick chorioallantoic membrane (CAM) without recruitment of inflammatory cells and induces vessel sprouting from chicken aorta rings. When added to CAM, subnanomolar concentrations of GM-CSF cause a rapid phosphorylation in tyrosine residues of JAK-2 persisting at least for 10 min. Furthermore, we show that signal transducers and activators of transcription (STAT)-3, but not STAT-5, also are phosphorylated for 30 min after GM-CSF stimulation. AG-490, a JAK-2 inhibitor, reduced in a dose-dependent manner the angiogenic effect of GM-CSF in CAM. These findings provide the first evidence that the JAK-2/STAT-3 pathway is activated in vivo and participates in vessel formation triggered by GM-CSF.
Valdembri
Donatella
D
Institute for Cancer Research and Treatment and Department of Genetics, Biology and Biochemistry, School of Medicine, University of Torino, Torino, Italy.
Serini
Guido
G
Vacca
Angelo
A
Ribatti
Domenico
D
Bussolino
Federico
F
D000482:Allantois / Q000098:blood supply / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000254:growth & development; D001808:Blood Vessels / Q000187:drug effects / Q000254:growth & development; D002642:Chick Embryo; D002645:Chickens; D002823:Chorion / Q000098:blood supply / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000254:growth & development; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D053614:Janus Kinase 2; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects*; D015534:Trans-Activators / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism
D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; D014443:Tyrosine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011505:Protein-Tyrosine Kinases; D053614:Janus Kinase 2