Blood Journal
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EGFL7 ligates αvβ3 integrin to enhance vessel formation

  1. Iva Nikolić1,2,
  2. Nevenka Dudvarski Stanković1,2,
  3. Frank Bicker1,2,
  4. Jeannette Meister1,2,
  5. Helene Braun3,
  6. Khader Awwad4,
  7. Jan Baumgart1,
  8. Kirsten Simon5,
  9. Serge C. Thal5,
  10. Chinmoy Patra3,
  11. Patrick N. Harter2,
  12. Karl H. Plate2,
  13. Felix B. Engel3,6,
  14. Stefanie Dimmeler7,
  15. Johannes A. Eble8,
  16. Michel Mittelbronn2,
  17. Michael K. Schäfer5,
  18. Benno Jungblut3,
  19. Emmanouil Chavakis7,
  20. Ingrid Fleming4, and
  21. Mirko H. H. Schmidt1,2
  1. 1Molecular Signal Transduction Laboratory at the Institute of Microscopic Anatomy and Neurobiology, Focus Program Translational Neuroscience (FTN), Johannes Gutenberg University School of Medicine, Mainz, Germany;
  2. 2Institute of Neurology (Edinger Institute), Goethe University School of Medicine, Frankfurt am Main, Germany;
  3. 3Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany;
  4. 4Institute for Vascular Signalling, Center for Molecular Medicine, Goethe University School of Medicine, Frankfurt am Main, Germany;
  5. 5Department of Anesthesiology, Johannes Gutenberg University School of Medicine, Mainz, Germany;
  6. 6Experimental Renal and Cardiovascular Research, Department of Nephropathology, Institute of Pathology, University of Erlangen-Nürnberg, Erlangen, Germany;
  7. 7Institute for Cardiovascular Regeneration, and
  8. 8Department of Vascular Matrix Biology, Center for Molecular Medicine, Goethe University School of Medicine, Frankfurt am Main, Germany

Key Points

  • EGFL7 promotes angiogenesis via its interaction with integrin αvβ3.

  • EGFL7 is involved in physiological and pathological angiogenesis.

Abstract

Angiogenesis, defined as blood vessel formation from a preexisting vasculature, is governed by multiple signal cascades including integrin receptors, in particular integrin αVβ3. Here we identify the endothelial cell (EC)-secreted factor epidermal growth factor-like protein 7 (EGFL7) as a novel specific ligand of integrin αVβ3, thus providing mechanistic insight into its proangiogenic actions in vitro and in vivo. Specifically, EGFL7 attaches to the extracellular matrix and by its interaction with integrin αVβ3 increases the motility of EC, which allows EC to move on a sticky underground during vessel remodeling. We provide evidence that the deregulation of EGFL7 in zebrafish embryos leads to a severe integrin-dependent malformation of the caudal venous plexus, pointing toward the significance of EGFL7 in vessel development. In biopsy specimens of patients with neurologic diseases, vascular EGFL7 expression rose with increasing EC proliferation. Further, EGFL7 became upregulated in vessels of the stroke penumbra using a mouse model of reversible middle cerebral artery occlusion. Our data suggest that EGFL7 expression depends on the remodeling state of the existing vasculature rather than on the phenotype of neurologic disease analyzed. In sum, our work sheds a novel light on the molecular mechanism EGFL7 engages to govern physiological and pathological angiogenesis.

  • Submitted November 25, 2011.
  • Accepted January 25, 2013.
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