title: Functional upregulation of the vascular endothelial growth factor receptor KDR by hypoxia.
abstract: BACKGROUND
  Vascular endothelial growth factor (VEGF) is a specific endothelial mitogen and chemoattractant that has been shown to be useful for inducing therapeutic angiogenesis in ischemic myocardium and found to stimulate mitogenicity and chemotaxis of endothelial cells through the receptor tyrosine kinase KDR. Although VEGF expression is upregulated by hypoxic stimuli, regulation of KDR remained unknown under these conditions.
  
  
  RESULTS
  With the use of human umbilical vein endothelial cells and transfected porcine aortic endothelial cells, KDR protein was found to be upregulated under hypoxic conditions (2% O2) in both cell types. This process of KDR upregulation was found to be reversible, was maximal after 24 hours of hypoxia, and was regulated on a posttranscriptional level. Furthermore, the susceptibility for VEGF-induced mitogenicity was enhanced under hypoxic conditions as shown by [3H]-thymidine incorporation assay. The activated state of increased VEGF function in hypoxic endothelial cells was associated with elevated tyrosine phosphorylation of KDR as demonstrated by anti-phosphotyrosine blot.
  
  
  CONCLUSIONS
  These data indicate that hypoxia stimulates VEGF-dependent signaling not only by upregulation of VEGF ligand but also by functional upregulation of a specific signaling receptor. Therefore, these data provide evidence that the endothelium plays an active role in hypoxia-induced angiogenesis.
authors.affiliation: Department of Internal Medicine II (Cardiology), Ulm University Medical Center, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Waltenberger
authors.forename: U
authors.initials: U
authors.lastname: Mayr
authors.forename: S
authors.initials: S
authors.lastname: Pentz
authors.forename: V
authors.initials: V
authors.lastname: Hombach
mesh_terms: D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D016228:Endothelial Growth Factors / Q000502:physiology; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D000860:Hypoxia / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008222:Lymphokines / Q000502:physiology; D008934:Mitogens / Q000502:physiology; D011499:Protein Processing, Post-Translational; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000378:metabolism*; D040262:Receptors, Vascular Endothelial Growth Factor; D015398:Signal Transduction; D013552:Swine; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D016228:Endothelial Growth Factors; D008222:Lymphokines; D008934:Mitogens; 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; D017871:Calcium-Calmodulin-Dependent Protein Kinases