Hypoxic Nitrite Reduction to Nitric Oxide: A Computational Modeling Approach

Nitric oxide (NO) is a powerful paracrine signaling molecule that plays a critical role in regulating blood vessel tone and vascular homeostasis. Deficiencies in endothelial NO production have been implicated in many cardiovascular and neurodegenerative diseases. Nitrite has been shown to act as a storage pool for NO that is relatively inactive in normoxia, but enzymatically reduced in hypoxia to restore lost NO. Recent experiments have identified a growing number of therapeutic applications of nitrite such as reduction of hypertension and cytoprotection against ischemia/reperfusion injury, but the mechanisms involved are not fully understood. We developed mathematical models to systematically analyze three major nitrite reduction pathways and characterize their NO elevation capabilities in microcirculatory vessel and tissue systems under various physiological, therapeutic, and pathological conditions. We also developed a microvascular network model to determine the effect of NO bioavailability on smooth muscle cell tone and the pressure-flow response. We examined how nitrite infused into the blood paradoxically induces vasodilation despite strong NO scavenging by hemoglobin. The model predicts that with hypoxia and moderate nitrite concentrations, a hypothesized N2O3 pathway can significantly preserve the NO produced by deoxyhemoglobin nitrite reductase in red blood cells and elevate NO reaching the smooth muscle cells. Microcirculatory vessel models were built to analyze tissue nitrite reductases deoxymyoglobin and aldehyde/xanthine oxidoreductase (AOR/XOR). This model predicts that cardiac myoglobin plays contrasting roles of scavenging NO during normoxia, but significantly elevating tissue and smooth muscle cell NO in acute ischemic, hypoxic, or acidotic conditions. Models of AOR and XOR in liver, kidney, and heart tissue predict that these nitrite reductases can produce a functionally significant increase in NO bioavailability with endogenous nitrite levels under extreme hypoxic conditions with acidic pH. Finally, we developed a dynamic computational model of a branching microcirculatory network with representative classes of resistance vessels to study the effect of endothelium-derived NO on the pressure-flow response. Our simulations predict the steady state and transient behavior of resistance vessels to perturbations in blood pressure, including effects of NO bioavailability on vascular tone. Together, these models contribute towards understanding the importance of nitrite reduction as a compensatory pathway for lost NO and the role of nitrite-NO interactions in microvascular flow regulation.Ph.D., Biomedical Engineering -- Drexel University, 201