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Notch1 activates angiogenic regulator Netrin4 in endothelial cells.

ABSTRACT: Netrin4 (NTN4) is a chemotropic factor that regulates angiogenesis. We found that endothelial expression of the activated, intracellular domain of Notch1 (NICD1), significantly up-regulated NTN4 mRNA as well as intracellular NTN4 protein in both transgenic mice and cultured human umbilical vein endothelial cells (HUVECs). Notch1 activation also increased NTN4 secretion from HUVECs. We subsequently demonstrated that NICD1 bound to CSL (CBF1, Suppressor of Hairless, Lag-1), a core component of Notch transcription complex, at the -53 element of the human NTN4 gene promoter. Loss of the -53 element compromised NICD1-induced NTN4 expression. Our results suggest a conserved role for Notch signalling in transcriptional regulation of endothelial NTN4.

SUBMITTER: Liu Q

PROVIDER: S-EPMC6484422 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Notch1 activates angiogenic regulator Netrin4 in endothelial cells.

Liu Qiang Q Allen Thaddeus D TD Song Wei W Wada Youichiro Y Lobe Corrinne G CG Liu Ju J

Journal of cellular and molecular medicine 20190219 5

Netrin4 (NTN4) is a chemotropic factor that regulates angiogenesis. We found that endothelial expression of the activated, intracellular domain of Notch1 (NICD1), significantly up-regulated NTN4 mRNA as well as intracellular NTN4 protein in both transgenic mice and cultured human umbilical vein endothelial cells (HUVECs). Notch1 activation also increased NTN4 secretion from HUVECs. We subsequently demonstrated that NICD1 bound to CSL (CBF1, Suppressor of Hairless, Lag-1), a core component of Not ...[more]

PMID: 30784178

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Project description:BackgroundEndothelial cells have been shown to mediate angiogenesis in ischemic injury sites and contribute to the repair of damaged tissues. However, the treatment of ischemic disease requires a significant number of endothelial cells, which are difficult to isolate from patients. Embryonic stem cells have been considered a potential source of therapeutic cells due to their unlimited self-renewal and pluripotent properties. With regard to vascular development, Notch1 has been established as a key regulator of the specification of arterial endothelial cells.MethodsUsing a doxycycline-induced expression system of the intracellular domain of Notch1, we explored the role of Notch1 in the differentiation of embryonic stem cells to arterial endothelial cells. The therapeutic effect of the arterial endothelial cells was investigated in a murine hindlimb ischemia model. The blood perfusion rate in the ischemic limb was determined by laser Doppler perfusion imaging, and vasculogenesis was quantified using immunocytochemistry.ResultsInduced expression of the intracellular domain of Notch1 increased the levels of endothelial markers, such as CD31 and VE-cadherin, in differentiated endothelial cells. Induction of intracellular domain of Notch1 stimulated expression of the arterial-type endothelial cell markers (Nrp1 and Ephrin B2), but not the venous-type endothelial cell markers (Nrp2 and Coup-TFII). In addition, overexpression of intracellular domain of Notch1 resulted in increased expression of CXCR4, a chemokine receptor involved in vascular development. Induction of intracellular domain of Notch1 increased endothelial tube formation and migration of differentiated endothelial cells. Intramuscular administration of Notch1-induced arterial endothelial cells was more effective than administration of the control endothelial cells in restoring the blood flow in an ischemic hindlimb mouse model. Transplantation of Notch1-induced arterial endothelial cells augmented the number of blood vessels and incorporation of endothelial cells into newly formed blood vessels.ConclusionsThese results suggest that Notch1 promotes endothelial maturation and arterial specification during the differentiation of embryonic stem cells to endothelial cells and increases the angiogenic potential of endothelial cells.

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Notch1 activates angiogenic regulator Netrin4 in endothelial cells.

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Notch1 activates angiogenic regulator Netrin4 in endothelial cells.

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