title: In silico modeling of shear-stress-induced nitric oxide production in endothelial cells through systems biology.
abstract: Nitric oxide (NO) produced by vascular endothelial cells is a potent vasodilator and an antiinflammatory mediator. Regulating production of endothelial-derived NO is a complex undertaking, involving multiple signaling and genetic pathways that are activated by diverse humoral and biomechanical stimuli. To gain a thorough understanding of the rich diversity of responses observed experimentally, it is necessary to account for an ensemble of these pathways acting simultaneously. In this article, we have assembled four quantitative molecular pathways previously proposed for shear-stress-induced NO production. In these pathways, endothelial NO synthase is activated 1), via calcium release, 2), via phosphorylation reactions, and 3), via enhanced protein expression. To these activation pathways, we have added a fourth, a pathway describing actual NO production from endothelial NO synthase and its various protein partners. These pathways were combined and simulated using CytoSolve, a computational environment for combining independent pathway calculations. The integrated model is able to describe the experimentally observed change in NO production with time after the application of fluid shear stress. This model can also be used to predict the specific effects on the system after interventional pharmacological or genetic changes. Importantly, this model reflects the up-to-date understanding of the NO system, providing a platform upon which information can be aggregated in an additive way.
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Koo
authors.forename: David
authors.initials: D
authors.lastname: Nordsletten
authors.forename: Renato
authors.initials: R
authors.lastname: Umeton
authors.forename: Beracah
authors.initials: B
authors.lastname: Yankama
authors.forename: Shiva
authors.initials: S
authors.lastname: Ayyadurai
authors.forename: Guillermo
authors.initials: G
authors.lastname: García-Cardeña
authors.forename: C Forbes
authors.initials: CF
authors.lastname: Dewey
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D042783:Endothelial Cells / Q000201:enzymology / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D009569:Nitric Oxide / Q000096:biosynthesis*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation; D033081:Shear Strength; D015398:Signal Transduction; D013312:Stress, Physiological; D049490:Systems Biology
chemical_list: D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D002118:Calcium