title: Cellular mechanisms underlying nitric oxide-induced vasodilation of descending vasa recta.
abstract: It has been observed that vasoactivity of explanted descending vasa recta (DVR) is modulated by intrinsic nitric oxide (NO) and superoxide (O(2)(-)) production (Cao C, Edwards A, Sendeski M, Lee-Kwon W, Cui L, Cai CY, Patzak A, Pallone TL. Am J Physiol Renal Physiol 299: F1056-F1064, 2010). To elucidate the cellular mechanisms by which NO, O(2)(-) and hydrogen peroxide (H(2)O(2)) modulate DVR pericyte cytosolic Ca(2+) concentration ([Ca](cyt)) and vasoactivity, we expanded our mathematical model of Ca(2+) signaling in pericytes. We incorporated simulations of the pathways that translate an increase in [Ca](cyt) to the activation of myosin light chain (MLC) kinase and cell contraction, as well as the kinetics of NO and reactive oxygen species formation and their effects on [Ca](cyt) and MLC phosphorylation. The model reproduced experimentally observed trends of DVR vasoactivity that accompany exposure to N(ω)-nitro-L-arginine methyl ester, 8-Br-cGMP, Tempol, and H(2)O(2). Our results suggest that under resting conditions, NO-induced activation of cGMP maintains low levels of [Ca](cyt) and MLC phosphorylation to minimize basal tone. This results from stimulation of Ca(2+) uptake from the cytosol into the SR via SERCA pumps, Ca(2+) efflux into the extracellular space via plasma membrane Ca(2+) pumps, and MLC phosphatase (MLCP) activity. We predict that basal concentrations of O(2)(-) and H(2)O(2) have negligible effects on Ca(2+) signaling and MLC phosphorylation. At concentrations above 1 nM, O(2)(-) is predicted to modulate [Ca(cyt)] and MCLP activity mostly by reducing NO bioavailability. The DVR vasoconstriction that is induced by high concentrations of H(2)O(2) can be explained by H(2)O(2)-mediated downregulation of MLCP and SERCA activity. We conclude that intrinsic generation of NO by the DVR wall may be sufficient to inhibit vasoconstriction by maintaining suppression of MLC phosphorylation.
authors.affiliation: Department of Chemical and Biological Engineering, Tufts University, Medford, MA 02155, USA. aurelie.edwards@tufts.edu
authors.forename: Aurélie
authors.initials: A
authors.lastname: Edwards
authors.forename: Chunhua
authors.initials: C
authors.lastname: Cao
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Pallone
mesh_terms: D000818:Animals; D002118:Calcium / Q000032:analysis / Q000378:metabolism; D003198:Computer Simulation; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D003497:Cyclic N-Oxides / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000378:metabolism; D007679:Kidney Medulla / Q000098:blood supply*; D008954:Models, Biological; D009219:Myosin-Light-Chain Kinase / Q000378:metabolism; D043263:Myosin-Light-Chain Phosphatase / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology*; D020286:Pericytes / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012077:Renal Artery / Q000187:drug effects / Q000502:physiology*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D013113:Spin Labels; D013873:Thionucleotides / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
chemical_list: D003497:Cyclic N-Oxides; D017382:Reactive Oxygen Species; D013113:Spin Labels; D013873:Thionucleotides; C083763:8-bromoguanosino-3',5'-cyclic monophosphorothioate; D009569:Nitric Oxide; D006861:Hydrogen Peroxide; D009219:Myosin-Light-Chain Kinase; D043263:Myosin-Light-Chain Phosphatase; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D006152:Cyclic GMP; D002118:Calcium; C001803:tempol; D019331:NG-Nitroarginine Methyl Ester