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This Article Full Text Full Text (PDF) All Versions of this Article: 289/2/H886    most recent 00216.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Yang, J. Articles by Robertson, C. S. Search for Related Content PubMed PubMed Citation Articles by Yang, J. Articles by Robertson, C. S.

Mathematical modeling of the nitric oxide/cGMP pathway in the vascular smooth muscle cell

Departments of ¹Bioengineering and ²Electrical and Computer Engineering, Rice University; and Departments of ³Anesthesiology and ⁴Neurosurgery, Baylor College of Medicine, Houston, Texas

Submitted 8 March 2004 ; accepted in final form 5 April 2005

The nitric oxide (NO)/cGMP pathway in the vascular smooth muscle cell (VSMC) is an important cellular signaling system for the regulation of VSMC relaxation. We present a mathematical model to investigate the underlying mechanisms of this pathway. The model describes the flow of NO-driven signal transduction: NO activation of soluble guanylate cyclase (sGC), sGC- and phosphodiesterase-catalyzed cGMP production and degradation, cGMP-mediated regulation of protein targets including the Ca²⁺-activated K⁺ (K_Ca) channel, and the myosin contractile system. Model simulations reproduce major NO/cGMP-induced VSMC relaxation effects, including intracellular Ca²⁺ concentration reduction and Ca²⁺ desensitization of myosin phosphorylation and force generation. Using the model, we examine several testable principles. 1) Rapid sGC desensitization is caused by end-product cGMP feedback inhibition; a large fraction of the steady-state sGC population is in an inactivated intermediate state, and cGMP production is limited well below maximum. 2) NO activates the K_Ca channel with both cGMP-dependent and -independent mechanisms; moderate NO concentration affects the K_Ca via the cGMP-dependent pathway, whereas higher NO concentration is accommodated by a cGMP-independent mechanism. 3) Chronic NO synthase inhibition may cause underexpressions of K⁺ channels including inward rectifier and K_Ca channels. 4) Ca²⁺ desensitization of the contractile system is distinguished from Ca²⁺ sensitivity of myosin phosphorylation. The model integrates these interactions among the heterogeneous components of the NO signaling system and can serve as a general modeling framework for studying NO-mediated VSMC relaxation under various physiological and pathological conditions. New data can be readily incorporated into this framework for interpretation and possible modification and improvement of the model.

cell signaling; smooth muscle relaxation; calcium desensitization; signal transduction; integrative model