Cellular mechanisms underlying nitric oxide-induced vasodilation of descending vasa recta

Edwards A, Cao C, Pallone TL. Cellular mechanisms underlying nitric oxide-induced vasodilation of descending vasa recta. Am J Physiol Renal Physiol 300: F441-F456, 2011. First published November 17, 2010; doi:10.1152/ajprenal.00499.2010.-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 (H2O2) modulate DVR pericyte cytosolic Ca2+ concentration ([Ca](cyt)) and vasoactivity, we expanded our mathematical model of Ca2+ 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-omega-nitro-L-arginine methyl ester, 8-Br-cGMP, Tempol, and H2O2. 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 Ca2+ uptake from the cytosol into the SR via SERCA pumps, Ca2+ efflux into the extracellular space via plasma membrane Ca2+ pumps, and MLC phosphatase (MLCP) activity. We predict that basal concentrations of O-2(-) and H2O2 have negligible effects on Ca2+ 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 H2O2 can be explained by H2O2-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.