Proper development and function of the cardiovascular system requires complex signaling between blood cells, vascular cells, and various support structures (for example, pericytes). The specification of blood and blood vessel cell fates from common precursors and establishment of a functional vascular network is driven by a genetically controlled pathway. This genetic program appears, however, to be regulated in turn by metabolic cues. We have demonstrated that an inability to modulate gene expression in response to low physiologic oxygen levels has profound effects on development of all components of the embryonic cardiovascular system (blood, vessels, heart, and placenta). These results suggest that oxygen levels function as critical developmental signals in many aspects of cardiovascular differentiation.
Activation of the hypoxia-inducible factor (HIF) transcriptional complex represents the primary molecular mechanism by which oxygen regulates gene expression. Interaction of HIF with its consensus DNA-binding site is required for hypoxia-induced target gene expression. We have identified more than 200 direct HIF target genes. These genes encode an array of proteins associated with cellular metabolism and survival, such as glycolytic enzymes, glucose transporters, and growth factors (for example, vascular endothelial growth factor, angiopoietins, transforming growth factor β, and platelet-derived growth factor β). By creating targeted mutations in murine HIF genes, we have begun to assess the developmental consequences of impaired oxygen signaling. Our results demonstrate an absolute requirement for HIF function in hematopoietic, vascular, cardiac, and placental development. These findings underscore the importance of oxygen signaling in mammalian ontogeny and offer potential targets for vascular and blood cell therapies. Recent data suggest that stem cells are also maintained in a pluripotent state in hypoxic microenvironments.
Low levels of oxygen cause profound adaptive effects on cellular metabolism and gene expression. However, this also includes a rapid and reversible inhibition of protein synthesis important for energy conservation in oxygen-deficient environments. Despite this global inhibition of protein synthesis, the translation of genes essential for cellular adaptation to hypoxia must continue. Although much is known about HIF transcriptional regulation, relatively little is known about how specific oxygen-regulated mRNAs are selectively translated in hypoxic cells. Given the poor vascular function of tumor blood vessels, cells within solid tumors frequently encounter oxygen deprivation. We hope to better define hypoxic translational control by cancer cells and develop novel therapies designed to combat the unique intracellular metabolism and physiology of these neoplasms.
This work was supported in part by grants from the National Institutes of Health and the Abramson Family Cancer Research Institute.
As of May 30, 2012