The growth factor Midkine antagonizes VEGF signaling in vitro and in vivo

Edward Htun van der Horst; Brendon T Frank; Lawrence Chinn; Angela Coxon; Shyun Li; Fanny Polesso; Anthony Slavin; Astrid Ruefli-Brasse; Holger Wesche

doi:10.1593/neo.07820

The growth factor Midkine antagonizes VEGF signaling in vitro and in vivo

Neoplasia. 2008 Apr;10(4):340-7. doi: 10.1593/neo.07820.

Authors

Edward Htun van der Horst¹, Brendon T Frank, Lawrence Chinn, Angela Coxon, Shyun Li, Fanny Polesso, Anthony Slavin, Astrid Ruefli-Brasse, Holger Wesche

Affiliation

¹ Department of Oncology, Amgen Inc., 1120 Veterans Blvd, South San Francisco, CA 94080, USA.

Abstract

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.

MeSH terms

Animals
Blotting, Western
Capillary Permeability
Chickens
Chorioallantoic Membrane / pathology
Corneal Neovascularization / metabolism
Endothelium, Vascular / cytology
Endothelium, Vascular / metabolism*
Enzyme-Linked Immunosorbent Assay
Female
Humans
In Vitro Techniques
Mice
Mice, Inbred BALB C
Midkine
Mitogen-Activated Protein Kinases / metabolism
Neoplasm Proteins / physiology
Nerve Growth Factors / physiology*
Phosphatidylinositol 3-Kinases / metabolism
Phosphorylation
Rats
Signal Transduction
Skin
Tissue Inhibitor of Metalloproteinase-2 / metabolism
Transforming Growth Factor alpha / metabolism
Tumor Necrosis Factor-alpha / metabolism
Vascular Endothelial Growth Factor A / antagonists & inhibitors*
Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

MDK protein, human
Neoplasm Proteins
Nerve Growth Factors
Transforming Growth Factor alpha
Tumor Necrosis Factor-alpha
VEGFA protein, human
Vascular Endothelial Growth Factor A
Tissue Inhibitor of Metalloproteinase-2
Midkine
Phosphatidylinositol 3-Kinases
Vascular Endothelial Growth Factor Receptor-2
Mitogen-Activated Protein Kinases