Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis.

By C. Ruhrberg, Holger Gerhardt, M. Golding, R. Watson, S. Ioannidou, H. Fujisawa, C. Betsholtz, D. Shima. Genes & Development, 2002

979 citations recorded by the source corpus.

Branching morphogenesis in the mammalian lung and Drosophila trachea relies on the precise localization of secreted modulators of epithelial growth to select branch sites and direct branch elongation, but the intercellular signals that control blood vessel branching have not been previously identified. We found that VEGF(120/120) mouse embryos, engineered to express solely an isoform of VEGF-A that lacks heparin-binding, and therefore extracellular matrix interaction domains, exhibited a specific decrease in capillary branch formation. This defect was not caused by isoform-specific differences in stimulating endothelial cell proliferation or by impaired isoform-specific signaling through the Nrp1 receptor. Rather, changes in the extracellular localization of VEGF-A in heparin-binding mutant embryos resulted in an altered distribution of endothelial cells within the growing vasculature. Instead of being recruited into additional branches, nascent endothelial cells were preferentially integrated within existing vessels to increase lumen caliber. The disruption of the normal VEGF-A concentration gradient also impaired the directed extension of endothelial cell filopodia, suggesting that heparin-binding VEGF-A isoforms normally provide spatially restricted stimulatory cues that polarize and thereby guide sprouting endothelial cells to initiate vascular branch formation. Consistent with this idea, we found opposing defects in embryos harboring only a heparin-binding isoform of VEGF-A, including excess endothelial filopodia and abnormally thin vessel branches in ectopic sites. We conclude that differential VEGF-A isoform localization in the extracellular space provides a control point for regulating vascular branching pattern.

Subfields: Cell Biology, Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/2a8ed602b62cb1e0eba62d4886ab8bd9a9d0bc53

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In Cell Biology

1. H. Gerber
2. Kenneth J. Hillan
3. W. Novotny
4. E. Dejana
5. R. Adams
6. D. Stainier
7. M. Swartz
8. K. Alitalo

In Molecular Biology

1. N. Ferrara
2. K. Alitalo
3. H. Gerber
4. R. Apte
5. Daniel Chen
6. Alicia S. Chung
7. W. Novotny
8. Rakesh K. Jain

In Pulmonary and Respiratory Medicine

1. H. Gerber
2. N. Ferrara

Citations in the corpus

• Role of platelet-derived growth factors in physiology and medicine. (2008, positive): “There, graded distribution of VEGF-A directs filopodial extensions and migratory behavior of endothelial tip cells, resulting in proper orientation of the angiogenic sprouts (Ruhrberg et al. 2002; Gerhardt et al. 2003).”
• Capturing complex 3D tissue physiology in vitro (2006, background): “The ECM also binds a wide variety of soluble growth factors and other effector molecules (for example, transforming growth factor-β ( TGFβ ), vascular-endothelial-cell growth factor ( VEGF ) and hepatocyte growth factor ( HGF”
• Molecular control of endothelial cell behaviour during blood vessel morphogenesis (2011, background): “For example, the heparan sulphate -binding isoform VEGFA165 (VEGFA164 in mice) is matrix associated and forms gradients that promote the extension of filopodia, the directional migration of ECs and the branching of blood vessel”
• Extracellular matrix and cell signalling: the dynamic cooperation of integrin, proteoglycan and growth factor receptor. (2011, background): “The precise deposition and expression of specific isoform of VEGF with a differential binding affinity for HSPG regulate endothelial cell proliferation, migration, differentiation and survival, which is necessary for appropriate pattern formation and tissue morphogenesis in mice (Ruhrberg et al. 200”
• VEGF in Signaling and Disease: Beyond Discovery and Development (2019, background): “VEGF gradients induce tip cells and promote the formation of filopodia (De Bock et al., 2013; Eilken and Adams, 2010; Gerhardt et al., 2003; Gerhardt, 2008; Hellström et al., 2007; Potente et al., 2011; Ruhrberg et al., 2002).”
• Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall. (2003, background): “In these mice, extracellular VEGF-A distribution becomes more widespread, leading to changes in endothelial sprouting and branching, and to the formation of abnormal vascular patterns (Ruhrberg et al. 2002).”
• Processing of VEGF-A by matrix metalloproteinases regulates bioavailability and vascular patterning in tumors (2005, methodology): “(2002) developed isoform-specific VEGF mice, revealing that VEGF-A isoforms play a critical role in the guidance of vascular patterning and in vessel diameter during development (Ruhrberg et al., 2002).”
• A Computational Tool for Quantitative Analysis of Vascular Networks (2011, methodology): “A well-established model system in the mouse, which allows characterization of developmental sprouting angiogenesis in embryos from E10, is the embryonic hindbrain [3].”
• Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer (2004, background): “There is now much evidence to indicate that VEGF 165 is the most physiologically relevant isofor”
• Endothelial cells dynamically compete for the tip cell position during angiogenic sprouting (2010, background): “Endothelial tip cells are induced and guided by an extracellular gradient of vascular endothelial growth factor (VEGF) -”
• Targeting the tumour vasculature: insights from physiological angiogenesis (2010, background): “A VEGFA gradient leads to the formation of a pioneering tip cell that is highly motile, and VEGFA concentration induces trailing stalk cell proliferation to form a new vessel sprou”