VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia.
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.
Gerhardt
Holger
H
Deparrment of Medical Biochemistry, University of Göteborg, Medicinaregatan 9A, Box 440, SE 405 30 Göteborg, Sweden.
Golding
Matthew
M
Fruttiger
Marcus
M
Ruhrberg
Christiana
C
Lundkvist
Andrea
A
Abramsson
Alexandra
A
Jeltsch
Michael
M
Mitchell
Christopher
C
Alitalo
Kari
K
Shima
David
D
Betsholtz
Christer
C
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques; D011554:Pseudopodia / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D012160:Retina / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D012161:Retinal Artery / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000187:drug effects / Q000378:metabolism
D016228:Endothelial Growth Factors; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2