Mathematical modeling of the nitric oxide/cGMP pathway in the vascular smooth muscle cell.
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+ (KCa) 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.
Yang
Jin
J
Department of Bioengineering, MS-366, Rice Univ., Houston, TX 77005, USA.
Clark
John W
JW
Bryan
Robert M
RM
Robertson
Claudia S
CS
D000818:Animals; D003198:Computer Simulation; D006152:Cyclic GMP / Q000378:metabolism*; D004553:Electric Conductivity; D025461:Feedback, Physiological; D006801:Humans; D008564:Membrane Potentials; D008955:Models, Cardiovascular; D009126:Muscle Relaxation / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism / Q000502:physiology; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism
D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D009569:Nitric Oxide; D006152:Cyclic GMP