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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

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