title: MEF2 transcription factors are key regulators of sprouting angiogenesis.
abstract: Angiogenesis, the fundamental process by which new blood vessels form from existing ones, depends on precise spatial and temporal gene expression within specific compartments of the endothelium. However, the molecular links between proangiogenic signals and downstream gene expression remain unclear. During sprouting angiogenesis, the specification of endothelial cells into the tip cells that lead new blood vessel sprouts is coordinated by vascular endothelial growth factor A (VEGFA) and Delta-like ligand 4 (Dll4)/Notch signaling and requires high levels of Notch ligand DLL4. Here, we identify MEF2 transcription factors as crucial regulators of sprouting angiogenesis directly downstream from VEGFA. Through the characterization of a Dll4 enhancer directing expression to endothelial cells at the angiogenic front, we found that MEF2 factors directly transcriptionally activate the expression of Dll4 and many other key genes up-regulated during sprouting angiogenesis in both physiological and tumor vascularization. Unlike ETS-mediated regulation, MEF2-binding motifs are not ubiquitous to all endothelial gene enhancers and promoters but are instead overrepresented around genes associated with sprouting angiogenesis. MEF2 target gene activation is directly linked to VEGFA-induced release of repressive histone deacetylases and concurrent recruitment of the histone acetyltransferase EP300 to MEF2 target gene regulatory elements, thus establishing MEF2 factors as the transcriptional effectors of VEGFA signaling during angiogenesis.
authors.affiliation: Ludwig Institute for Cancer Research Ltd., Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom.
authors.forename: Natalia
authors.initials: N
authors.lastname: Sacilotto
authors.affiliation: Ludwig Institute for Cancer Research Ltd., Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom.
authors.forename: Kira M
authors.initials: KM
authors.lastname: Chouliaras
authors.affiliation: Ludwig Institute for Cancer Research Ltd., Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom.
authors.forename: Leonid L
authors.initials: LL
authors.lastname: Nikitenko
authors.affiliation: Center for Cardiovascular Sciences, Albany Medical College, Albany, New York 12208, USA.
authors.forename: Yao Wei
authors.initials: YW
authors.lastname: Lu
authors.affiliation: Ludwig Institute for Cancer Research Ltd., Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: Fritzsche
authors.affiliation: Ludwig Institute for Cancer Research Ltd., Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom.
authors.forename: Marsha D
authors.initials: MD
authors.lastname: Wallace
authors.affiliation: Ludwig Institute for Cancer Research Ltd., Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom.
authors.forename: Svanhild
authors.initials: S
authors.lastname: Nornes
authors.affiliation: Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford OX1 3QX, United Kingdom.
authors.forename: Fernando
authors.initials: F
authors.lastname: García-Moreno
authors.affiliation: Ludwig Institute for Cancer Research Ltd., Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom.
authors.forename: Sophie
authors.initials: S
authors.lastname: Payne
authors.affiliation: Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 7LJ, United Kingdom.
authors.forename: Esther
authors.initials: E
authors.lastname: Bridges
authors.affiliation: Institute of Aging and Chronic Disease, University of Liverpool, Liverpool L7 8TX, United Kingdom.
authors.forename: Ke
authors.initials: K
authors.lastname: Liu
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Biggs
authors.affiliation: Ludwig Institute for Cancer Research Ltd., Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom.
authors.forename: Indrika
authors.initials: I
authors.lastname: Ratnayaka
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.
authors.forename: Shane P
authors.initials: SP
authors.lastname: Herbert
authors.affiliation: Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford OX1 3QX, United Kingdom.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Molnár
authors.affiliation: Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 7LJ, United Kingdom.
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Davies
authors.affiliation: Ludwig Institute for Cancer Research Ltd., Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom.
authors.forename: Gareth L
authors.initials: GL
authors.lastname: Bond
authors.affiliation: Institute of Aging and Chronic Disease, University of Liverpool, Liverpool L7 8TX, United Kingdom.
authors.forename: George
authors.initials: G
authors.lastname: Bou-Gharios
authors.affiliation: Center for Cardiovascular Sciences, Albany Medical College, Albany, New York 12208, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Schwarz
authors.affiliation: Ludwig Institute for Cancer Research Ltd., Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: De Val
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004625:Embryo, Nonmammalian; D042783:Endothelial Cells / Q000166:cytology* / Q000201:enzymology / Q000502:physiology*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D064326:MEF2 Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009389:Neovascularization, Pathologic / Q000235:genetics; D018919:Neovascularization, Physiologic / Q000235:genetics*; D054730:Protein Interaction Domains and Motifs; D012160:Retina / Q000196:embryology; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D015027:Zebrafish
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D064326:MEF2 Transcription Factors; D008565:Membrane Proteins; D042461:Vascular Endothelial Growth Factor A; C064045:delta protein; D006655:Histone Deacetylases
keywords: Dll4 regulation; HLX regulation; MEF2 transcription factors; sprouting angiogenesis