title: Hypoxia-induced arterial differentiation requires adrenomedullin and notch signaling.
abstract: Hypoxia (low oxygen) and Notch signaling are 2 important regulators of vascular development, but how they interact in controlling the choice between arterial and venous fates for endothelial cells during vasculogenesis is less well understood. In this report, we show that hypoxia and Notch signaling intersect in promotion of arterial differentiation. Hypoxia upregulated expression of the Notch ligand Dll4 and increased Notch signaling in a process requiring the vasoactive hormone adrenomedullin. Notch signaling also upregulated Dll4 expression, leading to a positive feedback loop sustaining Dll4 expression and Notch signaling. In addition, hypoxia-mediated upregulation of the arterial marker genes Depp, connexin40 (Gja5), Cxcr4, and Hey1 required Notch signaling. In conclusion, the data reveal an intricate interaction between hypoxia and Notch signaling in the control of endothelial cell differentiation, including a hypoxia/adrenomedullin/Dll4 axis that initiates Notch signaling and a requirement for Notch signaling to effectuate hypoxia-mediated induction of the arterial differentiation program.
authors: Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet, Huddinge, Sweden. fredrik.lanner@ki.se
authors: Fredrik
authors: F
authors: Lanner
authors: Kian Leong
authors: KL
authors: Lee
authors: Germán C
authors: GC
authors: Ortega
authors: Marcus
authors: M
authors: Sohl
authors: Xiujuan
authors: X
authors: Li
authors: Shaobo
authors: S
authors: Jin
authors: Emil M
authors: EM
authors: Hansson
authors: Lena
authors: L
authors: Claesson-Welsh
authors: Lorenz
authors: L
authors: Poellinger
authors: Urban
authors: U
authors: Lendahl
authors: Filip
authors: F
authors: Farnebo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D053607:Adrenomedullin / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001158:Arteries / Q000166:cytology* / Q000502:physiology; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation; D015687:Cell Hypoxia; D002478:Cells, Cultured; D058732:Embryoid Bodies / Q000378:metabolism; D042783:Endothelial Cells / Q000502:physiology; D005786:Gene Expression Regulation; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018919:Neovascularization, Physiologic; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D059467:Transcriptome; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051880:Receptors, Notch; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D053607:Adrenomedullin