Transcriptional control of endothelial tip cell function by Neuronal helix-loop-helix PAS (Per-ARNT-Sim) 4 -NPAS4-

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Many diseases -such as coronary artery disease, peripheral artery disease, diabetic proliferative retinopathy or malignant tumor growth- are characterized by inappropriate blood vessel growth and sprouting. Both, lack or overshooting vascular growth may have negative prognostic impact for the patient depending on the underlying disease. Vascular outgrowth is initiated and controlled by endothelial "tip cells", which also guide the growing blood vessel towards the region that is in need of perfusion, and eventually fuse with the respective tip cells from adjacent vascular sprouts. The regulatory mechanisms that control the formation and behavior of endothelial tip cells are not well understood. It has been established that sprouting of blood vessels obeys similar mechanisms as sprouting of other systems such as neurons or bronchial tubes. Based on these insights we hypothesized that the novel transcription factor Neuronal PAS4 (NPAS4) controls sprouting and fusion of endothelial tip cells. In drosophila melanogaster the homolog of NPAS4 dysfusion is expressed at the tip of bronchial tubes and its deletion results is a sprouting and fusion defect. In line with our hypothesis our previous and preliminary data indicate that NPAS4 is indeed expressed in endothelial cells. Functionally, lack of NPAS4 reduces endothelial cell sprouting in cultured endothelial cells whereas overexpression of NPAS4 has the opposite effect. As NPAS4 is a conserved protein among different species we were able to confirm these functional data using the in vivo zebrafish model. In this proposal we aim to: 1) investigate the expression and regulation of NPAS4 under physiologic and pathologic conditions, 2) elucidate its function in vascular sprouting and fusion in detail, 3) integrate NPAS4 in known signaling cascades of tip cell function and identify target proteins of this transcription factor. NPAS4 belongs to a family of transcription factors (HLH-PAS) which is involved in sensing of environmental cues such as hypoxia (HIF1a) or toxins (Ahr). Our preliminary data suggest that NPAS4 expression is highly sensitive to changes in extracellular K+ concentrations. Thus, NPAS4 may transduce ischemic signals into vascular responses and my therefore be an attractive therapeutic target.