EVL regulates VEGF receptor-2 internalization and signaling in developmental angiogenesis

  • Endothelial tip cells are essential for VEGF-induced angiogenesis, but underlying mechanisms are elusive. The Ena/VASP protein family, consisting of EVL, VASP, and Mena, plays a pivotal role in axon guidance. Given that axonal growth cones and endothelial tip cells share many common features, from the morphological to the molecular level, we investigated the role of Ena/VASP proteins in angiogenesis. EVL and VASP, but not Mena, are expressed in endothelial cells of the postnatal mouse retina. Global deletion of EVL (but not VASP) compromises the radial sprouting of the vascular plexus in mice. Similarly, endothelial-specific EVL deletion compromises the radial sprouting of the vascular plexus and reduces the endothelial tip cell density and filopodia formation. Gene sets involved in blood vessel development and angiogenesis are down-regulated in EVL-deficient P5-retinal endothelial cells. Consistently, EVL deletion impairs VEGF-induced endothelial cell proliferation and sprouting, and reduces the internalization and phosphorylation of VEGF receptor 2 and its downstream signaling via the MAPK/ERK pathway. Together, we show that endothelial EVL regulates sprouting angiogenesis via VEGF receptor-2 internalization and signaling.
Author:Joana Zink, Maike Frye, Timo Frömel, Claudia Carlantoni, David JohnORCiDGND, Danny Schreier, Andreas WeigertORCiDGND, Hebatullah Laban, Gabriela Salinas, Heike Stingl, Lea Günther, Rüdiger Popp, Jiong Hu, Benoit VanhollebekeORCiD, Hannes Schmidt, Amparo Acker-PalmerORCiDGND, Thomas Renné, Ingrid FlemingORCiD, Peter M. BenzORCiD
Parent Title (English):EMBO reports
Publisher:EMBO Press; Wiley
Place of publication:Heidelberg; Hoboken, NJ [u.a.]
Document Type:Article
Date of Publication (online):2021/01/29
Date of first Publication:2021/01/29
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2022/03/16
Tag:Ena/VASP proteins; VEGF receptor 2 internalization and signaling; endothelial cells; sprouting angiogenesis; tip cell filopodia formation
Issue:2, art. e48961
Page Number:19
First Page:1
Last Page:19
This work was supported by the Deutsche Forschungsgemeinschaft (SFB 834/A8 to PMB, SFB 834/A5 to IF, SFB 1039/B6 to AW, SFB 841/B8, and SFB 877/A11 to TR). PMB was also supported by the German Center for Cardiovascular Research (DZHK B14-028 SE). MF was supported by the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 840189 and the Werner-Otto-Stiftung Hamburg (8/95). The authors are indebted to Isabel Winter, Mechtild Piepenbrock-Gyamfi, Katharina Engel-Herbig, and Praveen Mathoor for expert technical assistance (all Johann Wolfgang Goethe University, Frankfurt, Germany). The authors acknowledge Kavi Devraj (Goethe University Frankfurt, Germany) for help with the isolation of brain endothelial cells, Michael Potente (MPI Bad Nauheim, Germany) for scientific input, Marcus Fruttinger (University College, London, UK) for providing pdgf-driven Cre mice, and Bernhard Nieswandt (University of Würzburg, Germany) for providing transgenic FLP-deleter mice. Open Access funding enabled and organized by ProjektDEAL.
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0