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Published online 16 June 2003. doi:10.1083/jcb.200302047
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© The Rockefeller University Press, 0021-9525/2003/6/1163 $5.00
The Journal of Cell Biology, Volume 161, Number 6, 1163-1177

Article

VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia



Holger Gerhardt1, Matthew Golding2, Marcus Fruttiger3, Christiana Ruhrberg2, Andrea Lundkvist1, Alexandra Abramsson1, Michael Jeltsch4, Christopher Mitchell5, Kari Alitalo4, David Shima2 and Christer Betsholtz1

1 Department of Medical Biochemistry, University of Göteborg, SE 405 30 Göteborg, Sweden
2 Endothelial Cell Biology Laboratory, Imperial Cancer Research Fund, London WC2A 3PX, UK
3 Wolfson Institute for Biomedical Research, University College London, London WC1E 6AU, UK
4 Molecular/Cancer Biology Laboratory, Haartman Institute and Ludwig Institute for Cancer Research, Biomedicum, 00014 Helsinki, Finland
5 Department of Obstetrics and Gynaecology, University of Nottingham, City Hospital, Nottingham, NG5 1PB, UK

Address correspondence to Christer Betsholtz, Dept. of Medical Biochemistry, University of Göteborg, Medicinaregatan 9A, Box 440, SE 405 30 Göteborg, Sweden. Tel.: 46-31-7733460. Fax: 46-31-416108. E-mail: christer.betsholtz{at}medkem.gu.se

Vascular endothelial growth factor (VEGF-A) is a major regulator of blood vessel formation and function. It controls several processes in endothelial cells, such as proliferation, survival, and migration, but it is not known how these are coordinately regulated to result in more complex morphogenetic events, such as tubular sprouting, fusion, and network formation. We show here that VEGF-A controls angiogenic sprouting in the early postnatal retina by guiding filopodial extension from specialized endothelial cells situated at the tips of the vascular sprouts. The tip cells respond to VEGF-A only by guided migration; the proliferative response to VEGF-A occurs in the sprout stalks. These two cellular responses are both mediated by agonistic activity of VEGF-A on VEGF receptor 2. Whereas tip cell migration depends on a gradient of VEGF-A, proliferation is regulated by its concentration. Thus, vessel patterning during retinal angiogenesis depends on the balance between two different qualities of the extracellular VEGF-A distribution, which regulate distinct cellular responses in defined populations of endothelial cells.

Key Words: VEGF; endothelial cell; filopodia; astrocyte; migration; proliferation

The online version of this article includes supplemental material.

David Shima's present address is Eyetech Research Center, Eyetech Pharmaceuticals Inc., 42 Cummings Park, Woburn, MA 01801.

* Abbreviations used in this paper: CNS, central nervous system; GFAP, glial fibrillary acidic protein; ILM, inner limiting membrane; P, postnatal day; PECAM, platelet–endothelial cell adhesion molecule; PlGF, placenta growth factor; VEGFR, vascular endothelial growth factor receptor.


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