title: VEGF-A/Notch-Induced Podosomes Proteolyse Basement Membrane Collagen-IV during Retinal Sprouting Angiogenesis.
abstract: During angiogenic sprouting, endothelial tip cells emerge from existing vessels in a process that requires vascular basement membrane degradation. Here, we show that F-actin/cortactin/P-Src-based matrix-degrading microdomains called podosomes contribute to this step. In vitro, VEGF-A/Notch signaling regulates the formation of functional podosomes in endothelial cells. Using a retinal neovascularization model, we demonstrate that tip cells assemble podosomes during physiological angiogenesis in vivo. In the retina, podosomes are also part of an interconnected network that surrounds large microvessels and impinges on the underlying basement membrane. Consistently, collagen-IV is scarce in podosome areas. Moreover, Notch inhibition exacerbates podosome formation and collagen-IV loss. We propose that the localized proteolytic action of podosomes on basement membrane collagen-IV facilitates endothelial cell sprouting and anastomosis within the developing vasculature. The identification of podosomes as key components of the sprouting machinery provides another opportunity to target angiogenesis therapeutically.
authors.affiliation: Departement Sciences du Vivant et de la Santé, Université de Bordeaux, 146 rue Léo Saignat, 33000 Bordeaux, France; INSERM, U1045, 2 rue Robert Escarpit, 33000 Bordeaux, France.
authors.forename: Pirjo
authors.initials: P
authors.lastname: Spuul
authors.affiliation: Departement Sciences du Vivant et de la Santé, Université de Bordeaux, 146 rue Léo Saignat, 33000 Bordeaux, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Daubon
authors.affiliation: Walter-Brendel Center of Experimental Medicine, Ludwig-Maximilians University, Marchioninistrasse 27, 81377 Munich, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Pitter
authors.affiliation: Departement Sciences du Vivant et de la Santé, Université de Bordeaux, 146 rue Léo Saignat, 33000 Bordeaux, France; INSERM, U1045, 2 rue Robert Escarpit, 33000 Bordeaux, France.
authors.forename: Florian
authors.initials: F
authors.lastname: Alonso
authors.affiliation: Departement Sciences du Vivant et de la Santé, Université de Bordeaux, 146 rue Léo Saignat, 33000 Bordeaux, France; INSERM, U1045, 2 rue Robert Escarpit, 33000 Bordeaux, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Fremaux
authors.affiliation: Departement Sciences du Vivant et de la Santé, Université de Bordeaux, 146 rue Léo Saignat, 33000 Bordeaux, France; INSERM, U1045, 2 rue Robert Escarpit, 33000 Bordeaux, France.
authors.forename: IJsbrand
authors.initials: I
authors.lastname: Kramer
authors.affiliation: Walter-Brendel Center of Experimental Medicine, Ludwig-Maximilians University, Marchioninistrasse 27, 81377 Munich, Germany. Electronic address: eloi.montanez@med.uni-muenchen.de.
authors.forename: Eloi
authors.initials: E
authors.lastname: Montanez
authors.affiliation: Departement Sciences du Vivant et de la Santé, Université de Bordeaux, 146 rue Léo Saignat, 33000 Bordeaux, France; INSERM, U1045, 2 rue Robert Escarpit, 33000 Bordeaux, France. Electronic address: elisabeth.genot@inserm.fr.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Génot
mesh_terms: D000199:Actins / Q000235:genetics; D000818:Animals; D001485:Basement Membrane / Q000378:metabolism; D024141:Collagen Type IV / Q000235:genetics* / Q000378:metabolism; D051356:Cortactin / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D055806:Microvessels / Q000254:growth & development / Q000378:metabolism*; D009024:Morphogenesis / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000235:genetics*; D000069261:Podosomes / Q000378:metabolism*; D059748:Proteolysis; D051880:Receptors, Notch / Q000378:metabolism; D012160:Retina / Q000254:growth & development / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D019061:src-Family Kinases / Q000235:genetics
chemical_list: D000199:Actins; D024141:Collagen Type IV; D051356:Cortactin; D051880:Receptors, Notch; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D019061:src-Family Kinases
keywords: Notch/Dll4 signaling; VEGF-A; actin; angiogenesis; basement membrane; collagen-IV; cytoskeleton; podosomes; retina; tip cells