MEF2 transcription factors are key regulators of sprouting angiogenesis

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 pro-angiogenic 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 VEGFA and Dll4/Notch signaling, and requires high levels of Notch ligand Delta-like ligand 4 (DLL4). Here, we identify MEF2 transcription factors as crucial regulators of sprouting angiogenesis directly downstream of VEGFA. Through the characterization of a Dll4 enhancer directing expression to endothelial cells at the angiogenic front, we find that MEF2 factors directly transcriptionally activate the expression of Dll4 and many other key genes upregulated during sprouting angiogenesis in both physiological and tumour vascularization. Unlike ETS-mediated regulation, MEF2 binding motifs are not ubiquitous to all endothelial gene enhancers and promoters, but are instead over-represented 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 acetyl-transferase EP300 to MEF2-target gene regulatory elements, thus establishing MEF2 factors as the transcriptional effectors of VEGFA signaling during angiogenesis.