title: VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling.
abstract: Angiogenesis, the growth of new blood vessels, involves specification of endothelial cells to tip cells and stalk cells, which is controlled by Notch signalling, whereas vascular endothelial growth factor receptor (VEGFR)-2 and VEGFR-3 have been implicated in angiogenic sprouting. Surprisingly, we found that endothelial deletion of Vegfr3, but not VEGFR-3-blocking antibodies, postnatally led to excessive angiogenic sprouting and branching, and decreased the level of Notch signalling, indicating that VEGFR-3 possesses passive and active signalling modalities. Furthermore, macrophages expressing the VEGFR-3 and VEGFR-2 ligand VEGF-C localized to vessel branch points, and Vegfc heterozygous mice exhibited inefficient angiogenesis characterized by decreased vascular branching. FoxC2 is a known regulator of Notch ligand and target gene expression, and Foxc2(+/-);Vegfr3(+/-) compound heterozygosity recapitulated homozygous loss of Vegfr3. These results indicate that macrophage-derived VEGF-C activates VEGFR-3 in tip cells to reinforce Notch signalling, which contributes to the phenotypic conversion of endothelial cells at fusion points of vessel sprouts.
authors: Molecular/Cancer Biology Laboratory, Institute for Molecular Medicine Finland, Research Programs Unit and Department of Pathology, Haartman Institute, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), 00014 University of Helsinki, Finland.
authors: Tuomas
authors: T
authors: Tammela
authors: Georgia
authors: G
authors: Zarkada
authors: Harri
authors: H
authors: Nurmi
authors: Lars
authors: L
authors: Jakobsson
authors: Krista
authors: K
authors: Heinolainen
authors: Denis
authors: D
authors: Tvorogov
authors: Wei
authors: W
authors: Zheng
authors: Claudio A
authors: CA
authors: Franco
authors: Aino
authors: A
authors: Murtomäki
authors: Evelyn
authors: E
authors: Aranda
authors: Naoyuki
authors: N
authors: Miura
authors: Seppo
authors: S
authors: Ylä-Herttuala
authors: Marcus
authors: M
authors: Fruttiger
authors: Taija
authors: T
authors: Mäkinen
authors: Anne
authors: A
authors: Eichmann
authors: Jeffrey W
authors: JW
authors: Pollard
authors: Holger
authors: H
authors: Gerhardt
authors: Kari
authors: K
authors: Alitalo
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012171:Retinal Vessels / Q000378:metabolism*; D012249:Rhombencephalon / Q000098:blood supply*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014161:Transduction, Genetic; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D042561:Vascular Endothelial Growth Factor B / Q000235:genetics / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism; D042643:Vascular Endothelial Growth Factor D / Q000235:genetics / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D000906:Antibodies; D051858:Forkhead Transcription Factors; D047428:Protein Kinase Inhibitors; D051880:Receptors, Notch; C467484:VEGFA protein, human; C467485:VEGFB protein, human; D042461:Vascular Endothelial Growth Factor A; D042561:Vascular Endothelial Growth Factor B; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D; C082078:mesenchyme fork head 1 protein; C467483:vascular endothelial growth factor C, mouse; D058539:Phosphatidylinositol 3-Kinase; D040321:Vascular Endothelial Growth Factor Receptor-3