title: VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia.
abstract: 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.
authors.affiliation: Deparrment of Medical Biochemistry, University of Göteborg, Medicinaregatan 9A, Box 440, SE 405 30 Göteborg, Sweden.
authors.forename: Holger
authors.initials: H
authors.lastname: Gerhardt
authors.forename: Matthew
authors.initials: M
authors.lastname: Golding
authors.forename: Marcus
authors.initials: M
authors.lastname: Fruttiger
authors.forename: Christiana
authors.initials: C
authors.lastname: Ruhrberg
authors.forename: Andrea
authors.initials: A
authors.lastname: Lundkvist
authors.forename: Alexandra
authors.initials: A
authors.lastname: Abramsson
authors.forename: Michael
authors.initials: M
authors.lastname: Jeltsch
authors.forename: Christopher
authors.initials: C
authors.lastname: Mitchell
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: David
authors.initials: D
authors.lastname: Shima
authors.forename: Christer
authors.initials: C
authors.lastname: Betsholtz
mesh_terms: 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
chemical_list: D016228:Endothelial Growth Factors; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2