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      VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia

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          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.

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          Most cited references 33

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          Pericyte loss and microaneurysm formation in PDGF-B-deficient mice.

          Platelet-derived growth factor (PDGF)-B-deficient mouse embryos were found to lack microvascular pericytes, which normally form part of the capillary wall, and they developed numerous capillary microaneurysms that ruptured at late gestation. Endothelial cells of the sprouting capillaries in the mutant mice appeared to be unable to attract PDGF-Rbeta-positive pericyte progenitor cells. Pericytes may contribute to the mechanical stability of the capillary wall. Comparisons made between PDGF null mouse phenotypes suggest a general role for PDGFs in the development of myofibroblasts.
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            Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid.

            Tumor ascites fluids from guinea pigs, hamsters, and mice contain activity that rapidly increases microvascular permeability. Similar activity is also secreted by these tumor cells and a variety of other tumor cell lines in vitro. The permeability-increasing activity purified from either the culture medium or ascites fluid of one tumor, the guinea pig line 10 hepatocarcinoma, is a 34,000- to 42,000-dalton protein distinct from other known permeability factors.
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              The molecular biology of axon guidance.

              Neuronal growth cones navigate over long distances along specific pathways to find their correct targets. The mechanisms and molecules that direct this pathfinding are the topics of this review. Growth cones appear to be guided by at least four different mechanisms: contact attraction, chemoattraction, contact repulsion, and chemorepulsion. Evidence is accumulating that these mechanisms act simultaneously and in a coordinated manner to direct pathfinding and that they are mediated by mechanistically and evolutionarily conserved ligand-receptor systems.

                Author and article information

                J Cell Biol
                The Journal of Cell Biology
                The Rockefeller University Press
                23 June 2003
                : 161
                : 6
                : 1163-1177
                [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
                Author notes

                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@ 123456medkem.gu.se

                Copyright © 2003, The Rockefeller University Press


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