Abstract
Adaptive responses to low Oxygen (O2) tension (hypoxia) are integral to embryogenesis, tumorigenesis, and tissue ischemia. Developing embryos begin to experience a hypoxic microenvironment promoting the development of the cardiovascular system. Early differentiation events focus the generation of Flk‐1, Brachyury double positive cardiovascular progenitor cells, hemangioblasts, which have hematopoietic, endothelial, and cardiomyocyte potential. Our model system utilizes embryonic stem (ES) cells, which can be cultured and differentiated under physiologic conditions (3 % O2) into embryoid bodies (EBs) mimicking early development Hypoxia Inducible Factor (HIF) is a major transcriptional player required for the temporal differentiation of these progenitor cells. We propose that HIF also plays a significant noncanonical role in mediating the generation and differentiation of hemangioblasts cells by interacting with the Notch signaling pathway. Using chemically and genetically modified mouse ES cells, differentiation experiments are being developed to explore the connection between these two pathways. Our present data demonstrate that hypoxia influences the expression of Notch receptors (Notch‐1 and ‐4), ligands (Delta‐4) and downstream Notch targets (Hrt‐1 and ‐2).Grant Funding Source: Supported by: R25‐HL03152 NHLBI Summer Research Program at CWRU
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