Computational Modeling of Enzymatic Nitric Oxide Production And Transport In The Microvasculature

Abstract

Nitric oxide (NO) can be released from multiple enzymatic and non-enzymatic sources to regulate O2 delivery. In this study, we formulated computational kinetic models to predict NO production rates from specific NO synthase (NOS) sources. Based on the analysis of biochemical pathways of neuronal NOS (NOS1) and endothelial NOS (NOS3) catalytic activities and the availability of NOS isoforms and substrates, our model predicted that the NO production rate from vascular endothelium expressing NOS3 is 0.005 – 0.1 μM/s and the rate from the nearby nerve tissues and interstitial mast cells expressing NOS1 is 0.4 – 1.2 μM/s under 100 μM O2 condition. We also calculated [NO] distribution around an arteriole with the predicted NO production rates and the topographical information on NOS isoforms. From our model, the major source determining the distribution of NO was NOS1 in the nerve fibers and mast cells close to arterioles, rather than the endothelial NOS3. Our models also predicted that O2 reduction significantly limits NO formation from NOS1 and thus NO exposure of vascular smooth muscle, opening the possibility that non-enzymatic NO becomes an important source under hypoxia. Moreover, the perivascular [NO] predicted by the models under normoxia was an order of magnitude lower than a number of experimental measurements, suggesting the existence of other enzymatic or non-enzymatic sources of NO in the microvasculature.