The growth factor Midkine antagonizes VEGF signaling in vitro and in vivo.
Midkine (MDK) is a heparin-binding growth factor involved in growth, survival, migration, and differentiation of various target cells and dysregulation of MDK signaling is implicated in a variety of inflammatory diseases and cancers. Although MDK has been reported to act on endothelial cells and to have proangiogenic effects, the exact role of MDK in angiogenesis is poorly defined. Here, we report that MDK is actually a modulator of angiogenesis and that it can abrogate the vascular endothelial growth factor A (VEGF-A)-induced proliferation of human microvascular endothelial cells in vitro through the downregulation of proangiogenic cytokines and through the upregulation of the antiangiogenic factor, tissue inhibitor of metalloproteinase 2. Phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR-2) and of downstream signaling molecules, such as phosphatidylinositol-3-kinase and mitogen-activated protein kinases, is also impaired. Moreover, MDK downregulates VEGF-A-induced neovascularization and vascular permeability in vivo. We propose a model in which MDK is a new modulator of the VEGF-A-VEGFR-2 axis.
van der Horst
Edward Htun
EH
Department of Oncology, Amgen Inc., 1120 Veterans Blvd, South San Francisco, CA 94080, USA.
Frank
Brendon T
BT
Chinn
Lawrence
L
Coxon
Angela
A
Li
Shyun
S
Polesso
Fanny
F
Slavin
Anthony
A
Ruefli-Brasse
Astrid
A
Wesche
Holger
H
D000818:Animals; D015153:Blotting, Western; D002199:Capillary Permeability; D002645:Chickens; D049033:Chorioallantoic Membrane / Q000473:pathology; D016510:Corneal Neovascularization / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D000078792:Midkine; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009363:Neoplasm Proteins / Q000502:physiology; D009414:Nerve Growth Factors / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D015398:Signal Transduction; D012867:Skin; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D016211:Transforming Growth Factor alpha / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
C066254:MDK protein, human; D009363:Neoplasm Proteins; D009414:Nerve Growth Factors; D016211:Transforming Growth Factor alpha; D014409:Tumor Necrosis Factor-alpha; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D019716:Tissue Inhibitor of Metalloproteinase-2; D000078792:Midkine; D019869:Phosphatidylinositol 3-Kinases; D040301:Vascular Endothelial Growth Factor Receptor-2; D020928:Mitogen-Activated Protein Kinases