Growth Factor Gradients in Vascular Patterning

  1. Derek J. Chadwick Organizer and
  2. Jamie Goode
  1. Andrea Lundkvist1,
  2. Sunyoung Lee2,
  3. Luisa Iruela-Arispe2,
  4. Christer Betsholtz Chair3 and
  5. Holger Gerhardt1,†

Published Online: 11 SEP 2007

DOI: 10.1002/9780470319413.ch15

Vascular Development: Novartis Foundation Symposium 283

Vascular Development: Novartis Foundation Symposium 283

How to Cite

Lundkvist, A., Lee, S., Iruela-Arispe, L., Betsholtz, C. and Gerhardt, H. (2007) Growth Factor Gradients in Vascular Patterning, in Vascular Development: Novartis Foundation Symposium 283 (eds D. J. Chadwick and J. Goode), John Wiley & Sons, Ltd, Chichester, UK. doi: 10.1002/9780470319413.ch15

Author Information

  1. 1

    Vascular Biology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK

  2. 2

    Molecular Biology Institute, Jonsson Comprehensive Cancer Center and Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, 611 Charles E. Young Drive Ea., Los Angeles, CA 99095, USA

  3. 3

    Laboratory of Vascular Biology, Division of Matrix Biology, House A3, Plan 4, Department of Medical Biochemistry and Biophysics, Scheeles vag 2, Karolinska Institutet, SE-171 77 Stockholm, Sweden

  1. This paper was presented at the symposium by Holger Gerhardt, to whom correspondence should be addressed.

Publication History

  1. Published Online: 11 SEP 2007
  2. Published Print: 20 JUL 2007

Book Series:

  1. Novartis Foundation Symposia

Book Series Editors:

  1. Novartis Foundation

ISBN Information

Print ISBN: 9780470034286

Online ISBN: 9780470319413

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Keywords:

  • growth factor gradients in vascular patterning;
  • matrix metalloproteinases (MMPs);
  • splicing of VEGF-A gene;
  • oxygen-induced retinopathy (OIR);
  • normal vascular patterning and VEGF-A gradients

Summary

Growth factor gradients regulate many developmental processes. VEGF-A is distributed in a graded fashion in growing tissues in order to direct sprouting of new vessels. Growth factor gradients can be formed by regulated production, retention, controlled release and degradation. VEGF-A production is controlled by hypoxia while its retention depends on the C-terminal heparin-binding motifs present in the longer splice-isoforms, VEGF164 and 188. This motif confers binding to the cell surface and the surrounding extracelluar matrix. The short isoform VEGF120 is diffusible and hence fails to direct endothelial tip cell migration. Conditional inactivation of heparan sulfate proteoglycans in the cells that produce VEGF results similarly in misguidance of the tip cells. Studying retinal developmental angiogenesis and pathological neovascularization side-by-side in the mouse retina, we find that endothelial tip cell guidance and stalk cell proliferation control are disrupted in neovascularization due to a loss of VEGFA retention. The cause for this is proteolytic cleavage of VEGF-A by matrix metalloproteases (MMP) derived mostly from macrophages infiltrating the ischaemic retinal areas. Genetic or pharmacological inhibition of macrophage infiltration or MMP activity can rescue guided revascularization at the expense of pre-retinal neovascularization. Disruption of VEGF-A gradients provides a novel concept for the mechanism underlying pathological patterning in ocular disease.