MEF2 transcription factors are key regulators of sprouting angiogenesis

Research output: Contribution to journalArticlepeer-review

Authors

  • Natalia Sacilotto
  • Kira M Chouliaras
  • Leonid L Nikitenko
  • Yao Wei Lu
  • Martin Fritzsche
  • Marsha D Wallace
  • Svanhild Nornes
  • Fernando García-Moreno
  • Sophie Payne
  • Esther Bridges
  • Ke Liu
  • Daniel Biggs
  • Indrika Ratnayaka
  • Shane P Herbert
  • Zoltán Molnár
  • Adrian L Harris
  • Benjamin Davies
  • George Bou-Gharios
  • John J Schwarz
  • Sarah De Val

Colleges, School and Institutes

External organisations

  • Ludwig Institute for Cancer Research Ltd., Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom.
  • Center for Cardiovascular Sciences, Albany Medical College, Albany, New York 12208, USA.
  • Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford OX1 3QX, United Kingdom.
  • Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 7LJ, United Kingdom.
  • University of Liverpool
  • The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom.
  • University of Manchester

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.

Bibliographic note

© 2016 Sacilotto et al.; Published by Cold Spring Harbor Laboratory Press.

Details

Original languageEnglish
Pages (from-to)2297-2309
Number of pages13
JournalGenes & Development
Volume30
Issue number20
Publication statusPublished - 15 Oct 2016

Keywords

  • Animals, Cells, Cultured, Embryo, Nonmammalian, Endothelial Cells/cytology, Enhancer Elements, Genetic/genetics, Gene Expression Regulation, Developmental, Histone Deacetylases/genetics, Humans, Intracellular Signaling Peptides and Proteins/genetics, MEF2 Transcription Factors/chemistry, Membrane Proteins/genetics, Mice, Neovascularization, Pathologic/genetics, Neovascularization, Physiologic/genetics, Protein Interaction Domains and Motifs, Retina/embryology, Signal Transduction, Vascular Endothelial Growth Factor A/metabolism, Zebrafish