Vegfa signals through ERK to promote angiogenesis, but not artery differentiation

Shin, Masahiro; Beane, Timothy J.; Quillien, Aurélie; Male, Ira; Zhu, Lihua Julie; Lawson, Nathan D.

doi:10.1242/dev.137919

Cited by 118 publications

(145 citation statements)

References 41 publications

(72 reference statements)

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“…In agreement with recent reports (Costa et al, 2016;Shin et al, 2016), pERK was enriched in angiogenic sprouts (i.e. intersomitic vessels) in developing zebrafish embryos, indicative of active MAPK/ERK signaling ( Fig.…”

Section: Dynamic Mapk/erk Signaling Regulates Gene Induction In Resposupporting

confidence: 93%

“…2B) and the number of ECs per sprout (Fig. S2B) were decreased, as demonstrated previously (Shin et al, 2016). At this dose, SL327 did not cause developmental delay or necrosis (Fig.…”

Section: Dynamic Mapk/erk Signaling Regulates Gene Induction In Resposupporting

confidence: 87%

“…6A,B). In addition, flt4, which is regulated by MAPK/ERK signaling during sprouting angiogenesis (Shin et al, 2016), was also dependent on p300/CBP and MEK (Fig. 6A,B).…”

Section: Erg Regulates a Network Of Constitutive And Vegf-inducible Gmentioning

confidence: 91%

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Dynamic regulation of VEGF-inducible genes by an ERK-ERG-p300 transcriptional network

et al. 2017

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The transcriptional pathways activated downstream of vascular endothelial growth factor (VEGF) signaling during angiogenesis remain incompletely characterized. By assessing the signals responsible for induction of the Notch ligand delta-like 4 (DLL4) in endothelial cells, we find that activation of the MAPK/ERK pathway mirrors the rapid and dynamic induction of DLL4 transcription and that this pathway is required for DLL4 expression. Furthermore, VEGF/ERK signaling induces phosphorylation and activation of the ETS transcription factor ERG, a prerequisite for DLL4 induction. Transcription of DLL4 coincides with dynamic ERG-dependent recruitment of the transcriptional co-activator p300. Genome-wide gene expression profiling identified a network of VEGF-responsive and ERG-dependent genes, and ERG chromatin immunoprecipitation (ChIP)-seq revealed the presence of conserved ERG-bound putative enhancer elements near these target genes. Functional experiments performed in vitro and in vivo confirm that this network of genes requires ERK, ERG and p300 activity. Finally, genome-editing and transgenic approaches demonstrate that a highly conserved ERG-bound enhancer located upstream of HLX (which encodes a transcription factor implicated in sprouting angiogenesis) is required for its VEGFmediated induction. Collectively, these findings elucidate a novel transcriptional pathway contributing to VEGF-dependent angiogenesis.

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Section: Dynamic Mapk/erk Signaling Regulates Gene Induction In Resposupporting

confidence: 93%

“…2B) and the number of ECs per sprout (Fig. S2B) were decreased, as demonstrated previously (Shin et al, 2016). At this dose, SL327 did not cause developmental delay or necrosis (Fig.…”

Section: Dynamic Mapk/erk Signaling Regulates Gene Induction In Resposupporting

confidence: 87%

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Dynamic regulation of VEGF-inducible genes by an ERK-ERG-p300 transcriptional network

et al. 2017

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“…For example, multiple calcium-regulated protein kinases are able to modulate HDAC binding to MEF2 factors, and phosphorylation by MAP kinases can activate MEF2 (Potthoff and Olson 2007;Ge et al 2009). The latter is particularly notable given that recent work implicates ERK as a specific effector of Vegfa signaling in the induction of angiogenic genes during sprouting (Shin et al 2016). Furthermore, research in skeletal muscle also demonstrated that the MEF2 proteins can compete with NICD for binding to the MAML coactivator (Shen et al 2006), suggesting that high levels of NICD in stalk cells may also have a repressive effect on MEF2 factors in the endothelium, reinforcing the lateral inhibition.…”

Section: Discussionmentioning

confidence: 97%

MEF2 transcription factors are key regulators of sprouting angiogenesis

et al. 2016

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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.

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“…In zebrafish, primary angiogenesis occurs when arterial sprouts emerge from the dorsal aorta (DA) from ∼22 hpf to give rise to the intersegmental arteries (aISV) in a process dependent on Kdr, Kdrl and Vegfa (Bahary et al, 2007;Covassin et al, 2006;Nasevicius et al, 2000;Olsson et al, 2006). During primary angiogenesis, blood vessel sprouting is led by tip cells, which express high levels of Flt4 (Vegfr3 in mammals) and display active Erk signaling (Gore et al, 2011;Shin et al, 2016a). In zebrafish, whole-genome duplication has resulted in the presence of two Vegfr2 paralogs, Kdr and Kdrl (Bussmann et al, 2008;Covassin et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Vegfd modulates both angiogenesis and lymphangiogenesis during zebrafish embryonic development

et al. 2017

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Vascular endothelial growth factors (VEGFs) control angiogenesis and lymphangiogenesis during development and in pathological conditions. In the zebrafish trunk, Vegfa controls the formation of intersegmental arteries by primary angiogenesis and Vegfc is essential for secondary angiogenesis, giving rise to veins and lymphatics. Vegfd has been largely thought of as dispensable for vascular development in vertebrates. Here, we generated a zebrafish vegfd mutant by genome editing. vegfd mutants display significant defects in facial lymphangiogenesis independent of vegfc function. Strikingly, we find that vegfc and vegfd cooperatively control lymphangiogenesis throughout the embryo, including during the formation of the trunk lymphatic vasculature. Interestingly, we find that vegfd and vegfc also redundantly drive artery hyperbranching phenotypes observed upon depletion of Flt1 or Dll4. Epistasis and biochemical binding assays suggest that, during primary angiogenesis, Vegfd influences these phenotypes through Kdr (Vegfr2) rather than Flt4 (Vegfr3). These data demonstrate that, rather than being dispensable during development, Vegfd plays context-specific indispensable and also compensatory roles during both blood vessel angiogenesis and lymphangiogenesis.

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Vegfa signals through ERK to promote angiogenesis, but not artery differentiation

Cited by 118 publications

References 41 publications

Dynamic regulation of VEGF-inducible genes by an ERK-ERG-p300 transcriptional network

Dynamic regulation of VEGF-inducible genes by an ERK-ERG-p300 transcriptional network

MEF2 transcription factors are key regulators of sprouting angiogenesis

Vegfd modulates both angiogenesis and lymphangiogenesis during zebrafish embryonic development

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