A VEGF/JAK2/STAT5 axis may partially mediate endothelial cell tolerance to hypoxia.
Perturbation of oxygen flow occurs in disease states such as diabetic retinopathy and cancer. To maintain oxygen homoeostasis, the mammalian microvascular endothelium undergoes a dramatic reorganization to assist in bringing oxygen and nutrients to oxygen-starved tissues. This process is termed angiogenesis and is common in certain cancers with hypoxic foci and in areas of focal ischaemia in the diabetic retina. In the present study, we report on the activation of the JAK2/STAT5 pathway (where JAK stands for Janus kinase and STAT stands for signal transduction and activator of transcription) by low oxygen in microvascular endothelial cells. This activation appears to occur downstream of VEGF (vascular endothelial growth factor), a well-known proangiogenic factor, and is related to repression of proapoptotic FAS(CD95)/FASL(CD95L). These results indicate that the JAK/STAT pathway may play a pivotal role during tumour-associated or retinal angiogenesis in which endothelial cell survival during tissue hypoxia is critical for maintaining either the growth of neoplasms or the inappropriate retinal neovascularization common in diabetic retinopathy.
Dudley
Andrew C
AC
Department of Medicine, St. Vincent's Hospital, University of Melbourne, Corner of Princes and Regent Streets, Fitzroy, VIC, 3065, Australia. andrew.dudley@childrens.harvard.edu
Thomas
David
D
Best
James
J
Jenkins
Alicia
A
D000818:Animals; D002417:Cattle; D015687:Cell Hypoxia / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism; D002474:Cell-Free System; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology*; D053222:Fas Ligand Protein; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D053614:Janus Kinase 2; D008562:Membrane Glycoproteins / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D048069:Tumor Necrosis Factors / Q000378:metabolism; D020032:Tyrphostins; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D050799:STAT5 Transcription Factor; D048069:Tumor Necrosis Factors; D020032:Tyrphostins; D042461:Vascular Endothelial Growth Factor A; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D011505:Protein-Tyrosine Kinases; D053614:Janus Kinase 2; D010100:Oxygen