The neuronal transcription factor NPAS4 is a strong inducer of sprouting angiogenesis and tip cell formation

<span class="paragraphSection"><div class="boxTitle">Rationale</div>Regarding branching morphogenesis, neurogenesis and angiogenesis share common principle mechanisms and make use of the same molecules. Therefore, the investigation of neuronal molecules involved in vascular morphogenesis provides new possibilities for pro-angiogenic approaches in cardiovascular diseases.<div class="boxTitle">Objective</div>In this study, we investigated the role of the neuronal transcription factor NPAS4 in angiogenesis.<div class="boxTitle">Methods and results</div>Here, we demonstrate that the neuronal transcription factor NPAS4 is expressed in endothelial cells of different origin using reverse transcription PCR and western blot analysis. To investigate how NPAS4 affects endothelial cell function, NPAS4 was overexpressed by plasmid transfection or depleted from human umbilical vein endothelial cells (HUVECs) by specific siRNAs. <span style="font-style:italic;">In vitro</span> HUVEC sprouting assays showed that sprouting and branching of endothelial cells was enhanced by NPAS4 overexpression. Consistently, silencing of NPAS4 resulted in reduced HUVEC sprouting and branching. Mechanistically, we identified as target gene vascular endothelial adhesion molecule VE-cadherin to be involved in the pro-angiogenic function of NPAS4. In endothelial cell mosaic spheroid sprouting assays, NPAS4 was involved in tip cell formation. <span style="font-style:italic;">In vivo</span> experiments in mouse and zebrafish confirmed our <span style="font-style:italic;">in vitro</span> findings. NPAS4-deficient mice displayed reduced ingrowth of endothelial cells in the Matrigel plug assay. Consistent with a regulatory role of NPAS4 in endothelial cell function silencing of NPAS4 in zebrafish by specific morpholinos resulted in perturbed intersegmental vessels growth.<div class="boxTitle">Conclusions</div>NPAS4 is expressed in endothelial cells, regulates VE-cadherin expression and regulates sprouting angiogenesis.</span>

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