Theoretical analysis of biochemical pathways of nitric oxide release from vascular endothelial cells

Model Status

This CellML model runs in OpenCell and COR and is known to be mathematically consistent with the publication it was based on. The units are consistent. An additional variable and equation has been added to allow the CellML model to reproduce Figure 2 of the publication. The three different graphs of this figure can be produced by altering the variable 'Fe3' in the 'Fe3' component (this variable represents the concentration of eNOS in its Fe3+ bound state) to 0.045, 0.030 or 0.015 micromolar. In this particular version of the model it has been set to 0.045.

Model Structure

ABSTRACT: Vascular endothelium expressing endothelial nitric oxide synthase (eNOS) produces nitric oxide (NO), which has a number of important physiological functions in the microvasculature. The rate of NO production by the endothelium is a critical determinant of NO distribution in the vascular wall. We have analyzed the biochemical pathways of NO synthesis and formulated a model to estimate NO production by the microvascular endothelium under physiological conditions. The model quantifies the NO produced by eNOS based on the kinetics of NO synthesis and the availability of eNOS and its intracellular substrates. The predicted NO production from microvessels was in the range of 0.005-0.1 microM/s. This range of predicted values is in agreement with some experimental values but is much lower than other rates previously measured or estimated from experimental data with the help of mathematical modeling. Paradoxical discrepancies between the model predictions and previously reported results based on experimental measurements of NO concentration in the vicinity of the arteriolar wall suggest that NO can also be released through eNOS-independent mechanisms, such as catalysis by neuronal NOS (nNOS). We also used our model to test the sensitivity of NO production to substrate availability, eNOS concentration, and potential rate-limiting factors. The results indicated that the predicted low level of NO production can be attributed primarily to a low expression of eNOS in the microvascular endothelial cells.

Schematic diagram of the mathematical model. Pathway of nitric oxide (NO) synthesis catalysed by endothelial nitric oxide synthase (eNOS, or eNOS3). The heme iron (Fe) is the main catalysis site and is used to represent the enzyme in this figure and also in the model. The heme ion of eNOS binds L-arginine (Arg), hydroxyl-L-arginine (NOHA), and oxygen (O2), and undergoes a series of oxygenation and reduction reactions.

The original paper reference is cited below:

Theoretical analysis of biochemical pathways of nitric oxide release from vascular endothelial cells, Kejing Chen and Aleksander S. Popel, 2006, Free Radical Biology and Medicine , 41, 668-680. PubMed ID: 16864000