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Notch and Hypoxia Inducible Factor Cooperate in the Generation of Hemangioblast and in Sprouting Angiogenesis
Author(s) -
Calderon Alexander,
RamírezBergeron Diana
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.896.15
Subject(s) - hemangioblast , notch signaling pathway , microbiology and biotechnology , sprouting angiogenesis , embryonic stem cell , cell fate determination , angiogenesis , biology , progenitor cell , hypoxia inducible factors , haematopoiesis , sprouting , stem cell , signal transduction , transcription factor , neovascularization , cancer research , genetics , botany , gene
Adaptive responses to low Oxygen tension (hypoxia) are integral to embryogenesis, tumorigenesis, and tissue ischaemia, and during embryonic development, promoting the development of the cardiovascular system. Hypoxic responses mediated by Hypoxia Inducible Factor (HIF) as well as Notch signals mediated by the ligand Delta‐4 (Dll‐4) stimulate the generation of cardiovascular progenitor cells, hemangioblasts, and their subsequent differentiation into haematopoietic and endothelial cells (ECs). In addition to Notch's involvement in cell‐cell signaling, cell‐fate determination, and binary cell fate decision, it promotes sprouting angiogenesis. Because of the known physical interaction between cleaved‐Notch (NICD) and the HIFα subunit, we propose that noncanonical biochemical crosstalk between these two pathways are critical during these vascular events. We utilize a differentiation system with mouse Embryonic Stem Cells (mESC) to analyze the cooperation of Notch and HIF during the early emergence of hemangioblasts. We also manipulate the activity of HIF and Notch to dissect the effects of hypoxia on Notch‐dependent sprouting of ECs. To do this we utilize genetic (DNMM) and biochemical (γ‐secretase inhibitor, and hypoxia) approaches to ascertain the biological responses of our systems. Our data thus far shows differential transcriptional regulation of Notch downstream targets, specifically down regulation of Hrt‐1 and Hrt‐2 , up regulation of Notch ligands Jag‐1 and Dll‐4 and down regulation of Vegf . There are also differences in sprouting assays concerning the number of sprouts and length of sprouts under various biochemical conditions.