Unknown,Transcriptomics,Genomics,Proteomics

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Hypoxia-induced Arterial Differentiation Requires Adrenomedullin and Notch Signaling

ABSTRACT: Hypoxia (low oxygen) and Notch signaling are two 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 increases Notch signaling, in a process requiring the vasoactive hormone adrenomedullin but not endogenous VEGF. Notch signaling also upregulated Dll4 expression, leading to a positive feedback loop sustaining Dll4 expression and Notch signaling. In addition, functional Notch signaling was required for hypoxia to upregulate the arterial marker genes Depp, connexin40 (Gja5), Cxcr4 and Hey1. 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 hypoxiamediated induction of the arterial differentiation program. 12 microarray samples consisting of >50,000 FACS sorted CD31+ cells purified from wild type mouse CCE ES cells that were differentiated into the endothelial lineages in 3 biological replicates. The ES cells were subjected to embryoid body formation over 4 days in hanging drop cultures, FACS sorted for Flk1 positive vascular progenitors cells and plated for a further 4 days in normoxia (21% oxygen) or hypoxia (1.5-2% oxygen) with or without 4 umol/l gamma-secretase inhibitor L-685.458.

ORGANISM(S): Mus musculus

SUBMITTER: Kian Leong LEE

PROVIDER: E-GEOD-35894 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Hypoxia-induced arterial differentiation requires adrenomedullin and notch signaling.

Lanner Fredrik F Lee Kian Leong KL Ortega Germán C GC Sohl Marcus M Li Xiujuan X Jin Shaobo S Hansson Emil M EM Claesson-Welsh Lena L Poellinger Lorenz L Lendahl Urban U Farnebo Filip F

Stem cells and development 20130212 9

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. ...[more]

PMID: 23379656

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Hypoxia-induced Arterial Differentiation Requires Adrenomedullin and Notch Signaling

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Hypoxia-induced arterial differentiation requires adrenomedullin and notch signaling.

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