Hypoxia Influences the Vascular Expansion and Differentiation of Embryonic Stem Cell

"Hypoxia Influences the Vascular Expansion and Differentiation of Embryonic Stem Cell Cultures Through the Temporal Expression of VEGF- Receptors in an ARNT-Dependent Manner"
Stem Cells. 2010 Feb 4
Han Y, Kuang SZ, Gomer A, Ramirez-Bergeron DL.
Case Cardiovascular Research Institute and University Hospitals Harrington-McLaughlin Heart & Vascular Institute, Case Western Reserve University School of Medicine, Cleveland

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Adaptive responses to low oxygen (O(2)) tension (hypoxia) are mediated by the heterodimeric transcription factor Hypoxia Inducible Factor (HIF). When stabilized by hypoxia, bHLH-PAS alpha- and beta- (HIF-1beta or ARNT) HIF complex regulate the expression of multiple genes including vascular endothelial growth factor (VEGF). In order to address the mechanism(s) through which hypoxia contributes to blood vessel development, we utilized embryonic stem cell (ESC) differentiation cultures that develop into embryoid bodies (EBs) mimicking early embryonic development. Significantly, low O(2) levels promote vascular development and maturation in wild type (WT) ESC cultures measured by an increase in numbers of CD31(+) endothelial cells (ECs) and sprouting angiogenic EBs but refractory in Arnt(-/-) and Vegf(-/-) ESC cultures. Thus, we propose that hypoxia promotes the production of ECs and contributes to the development and maturation of vessels. Our findings further demonstrate that hypoxia alters the temporal expression of VEGF receptors Flk-1 (VEGFR-2) and the membrane and soluble forms of the antagonistic receptor Flt-1 (VEGFR-1). Moreover, these receptors are distinctly expressed in differentiating Arnt(-/-) and Vegf(-/-) EBs. These results support existing models wherein VEGF signaling is tightly regulated during specific biological events, but also provide important novel evidence that, in response to physiological hypoxia, HIF mediates a distinct stoichiometric pattern of VEGF receptors throughout EB differentiation analogous to the formation of vascular networks during embryogenesis.

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