Shear-Induced Nitric Oxide Production by Endothelial Cells

TL;DR

This paper develops a biochemical model explaining how wall shear stress activates endothelial cells to produce nitric oxide, involving mechanotransducers, calcium signaling, kinase activity, and feedback regulation, predicting biphasic NO production dynamics.

Contribution

The model integrates multiple mechanotransduction pathways and feedback mechanisms to predict NO production dynamics in endothelial cells under shear stress, a novel comprehensive approach.

Findings

Predicts rapid initial calcium influx within 1-5 minutes

Shows biphasic NO production with initial spike and sustained phase

Demonstrates nonlinear, transient eNOS activation behavior

Abstract

We present a biochemical model of the wall shear stress (WSS)-induced activation of endothelial nitric oxide synthase (eNOS) in an endothelial cell (EC). The model includes three key mechanotransducers: mechanosensing ion channels, integrins and G-protein-coupled receptors. The reaction cascade consists of two interconnected parts. The first is rapid activation of calcium, which results in formation of calcium-calmodulin complexes, followed by recruitment of eNOS from caveolae. The second is phosphoryaltion of eNOS by protein kinases PKC and AKT. The model also includes a negative feedback loop due to inhibition of calcium influx into the cell by cyclic guanosine monophosphate (cGMP). In this feedback, increased nitric oxide (NO) levels cause an increase in cGMP levels, so that cGMP inhibition of calcium influx can limit NO production. The model was used to predict the dynamics of NO production by an EC subjected to a step increase of WSS from zero to a finite physiologically relevant value. Among several experimentally observed features, the model predicts a highly nonlinear, biphasic transient behavior of eNOS activation and NO production: a rapid initial activation due to the very rapid influx of calcium into the cytosol (occurring within 1 to 5 minutes) is followed by a sustained period of activation due to protein kinases.