Oxygen Sensing in the Circulation: "Cross Talk" Between Red Blood Cells and the Vasculature

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Abstract
Oxygen (O2) sensing in blood and regulation of microvascular tone appear to involve hemoglobin (Hb) conformational changes resulting from O2 desaturation. This observation has prompted the thought that Hb functions as both an O2 sensor and regulator of microvasular blood flow to meet local tissue oxygen demand. The mechanism(s) by which this is accomplished has recently been the subject of increasing debate. Three primary hypotheses are described within the literature and include release of adenosine 5'-triphosphate by red blood cells (RBCs), release of S-nitrosylated molecules from RBCs originally bound to β93 cysteine residues of oxyHb, and nitrite conversion and storage of nitric oxide by Hb at the site of ferric (Fe3+) and ferrous (Fe2+) Hb. Within extravascular cells, the global regulator of oxygen homeostasis is hypoxia-inducible factor-1 (HIF- 1). This transcriptional factor is tightly regulated by O2 and cellular redox-sensitive mechanisms. HIF-1 activation is responsible for the up-regulation of proteins, which increase O2 supply. We believe that there are important and yet unexplored mechanisms by which RBCs can directly or indirectly communicate via redox intermediates with extravascular sites as part of the global O2 sensing mechanism. Antioxid. Redox Signal. 6, 1000–1010.