Nitric oxide formation versus scavenging: the red blood cell balancing act

Abstract

Nitric oxide (NO) is a key modulator of vascular homeostasis controlling critical functions related to blood flow, respiration, cell death and proliferation, and protecting the vasculature from pro-inflammatory and coagulative stresses. Inhibition of NO formation, and/or diversion of NO away from its physiological signalling targets lead to dysregulated NO bioavailability, a hallmark of numerous vascular and pulmonary diseases. Current concepts suggest that the balance between NO formation and NO scavenging is critical in disease development, with the corollary being that redressing the balance offers a target for therapeutic intervention. Evidence presented over the last two decades has seen red blood cells (RBCs) and haemoglobin specifically emerge as prominent effectors in this paradigm. In this symposium review article, we discuss recent insights into the mechanisms by which RBCs may modulate the balance between NO-formation and inhibition. We discuss how these mechanisms may become dysfunctional to cause disease, highlight key questions that remain, and discuss the potential impact of these insights on therapeutic opportunities.

Figure 1. Current models for how RBCs can inhibit and stimulate NO signalling

Shown is how haemoglobin oxygen sensing may be coupled to NO scavenging (by intact or cell-free haemoglobin), or formation (from deoxyhaemoglobin-mediated nitrite reduction or ATP release and subsequent eNOS activation) to control NO bioavailability in the vasculature. Also shown is the concept that nitrite reduction to elicit NO signalling during hypoxia may occur by tissues independent of RBCs, but RBCs can affect this process by controlling nitrite concentration via oxidation to nitrate.