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MEF2 transcription factors are key regulators of sprouting angiogenesis

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


Natalia Sacilotto

Kira M. Chouliaras

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

Gareth L. Bond

George Bou-Gharios

John J. Schwarz

Sarah De Val



© 2016 Sacilotto et al. 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 factorA (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.


Sacilotto, N., Chouliaras, K. M., Nikitenko, L. L., Lu, Y. W., Fritzsche, M., Wallace, M. D., …De Val, S. (2016). MEF2 transcription factors are key regulators of sprouting angiogenesis. Genes & development, 30(20), 2297-2309.

Journal Article Type Article
Acceptance Date Sep 16, 2016
Online Publication Date Nov 8, 2016
Publication Date Oct 15, 2016
Deposit Date Jan 10, 2018
Publicly Available Date Jan 18, 2018
Journal Genes and Development
Print ISSN 0890-9369
Electronic ISSN 1549-5477
Publisher Cold Spring Harbor Laboratory Press
Peer Reviewed Peer Reviewed
Volume 30
Issue 20
Pages 2297-2309
Keywords Developmental Biology; Genetics
Public URL
Copyright Statement © 2016 Sacilotto et al.; Published by Cold Spring Harbor Laboratory Press


Published article (2.1 Mb)

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

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