MEF2 transcription factors are key regulators of sprouting angiogenesis

Natalia Sacilotto, Kira Chouliaras, Leonid Nikitenko, Yao Wei Lu, Martin fritzsche, Marsha Wallace, Svanhild Nornes, Fernando García-Moreno, sophie payne, Esther Bridges, ke Liu, Daniel Biggs, Indrika Ratnayaka, Shane Herbert, Zoltán Molnár, Adrian Harris, Benjamin Davies, Gareth Bond, George Bou-Gharios, John SchwarzSarah De Val

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Pages (from-to)2297-2309
JournalGenes and development
Issue number20
Publication statusPublished - 31 Dec 2016


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