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

Abstract

signaling and MLC phosphorylation. At concentrations above 1 nM, O 2 Ϫ is predicted to modulate [Cacyt] and MCLP activity mostly by reducing NO bioavailability. The DVR vasoconstriction that is induced by high concentrations of H 2O2 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. calcium signaling; hydrogen peroxide; superoxide; vascular smooth muscle NITRIC OXIDE (NO) acts as a local vasodilator in the renal medulla and plays an important role in the maintenance of medullary perfusion, medullary oxygenation, and blood pressure. Chronic inhibition of nitric oxide synthase (NOS) reduces medullary blood flow (MBF) and is associated with sodium retention and the development of hypertension (8, 41). Whereas NO increases MBF by promoting the vasodilation of descending vasa recta (DVR) or juxtamedullary arterioles, superoxide (O 2 Ϫ ) and hydrogen peroxide (H 2 O 2 ) act to reduce MBF by mechanisms that remain to be fully elucidated (17,37). In addition, NO inhibits, whereas O 2 Ϫ enhances, thick ascending limb sodium reabsorption (23). Hence, interactions between NO and O 2 Ϫ likely contribute to the long-term control of blood pressure; when the balance between these two radicals is shifted in favor of O 2 Ϫ (such as in diabetes and atherosclerosis, conditions that promote oxidative stress), renal vasoconstriction and tubular reabsorption increase, favoring hypertension (17).In a recent microperfusion study of DVR (4), we showed that intrinsic production of NO and reactive oxygen species (ROS) affects DVR vasoactivity. To elucidate the cellular pathways by which NO, O 2 Ϫ , and H 2 O 2 modulate DVR contraction, in the present study we expanded our mathematical model of Ca 2ϩ signaling in DVR pericytes to account for the effects of NO and ROS and to predict the degree of vessel contraction.Smooth muscle contraction is initiated by an increase in cytosolic Ca 2ϩ concentration ([Ca] cyt ). Increased binding of Ca 2ϩ to calmodulin (CaM) activates myosin light chain kinase (MLCK), which then phosphorylates myosin light chains (MLC) in the presence of ATP, thereby increasing the cycling rate of actin-myosin cross-bridge formation and generating the active force needed for muscle contraction. Most of the vasodilatory effects of NO on smooth muscle cells appear to be mediated by cGMP. Activity of the NO/cGMP pathway favors reduction in the fraction of phosphorylated myosin, via two different mechanisms: 1) an increase in the activity of myosin light chain phosphatase (MLCP), and 2) modulation of Ca 2ϩ transport that lowers [Ca] cyt , decreases Ca 2ϩ binding to CaM, and thereby reduces MLCK activity.We incorporated these and other signaling pathways in our mathematical model of DVR pericytes as described in MODEL DESCRIPTION. The data on which this and prior versions of the model are based have been largely derived from studies of DVR peric...

Renal Endothelial Injury and Microvascular Dysfunction in Acute Kidney Injury

“…Various endogenous stimuli, acetylcholine [20], angiotensin-II, adenosine triphosphate (ATP), endothelin-1, noradrenaline, UTP and vasopressin, have been shown to evoke pericyte mediated vasoconstriction of vasa recta. Besides peptides and hormones, free radicals and reactive oxygen species (ROS) have also been implicated in the regulation of medullary blood flow [21, 22]. All three forms of nitric oxide synthase (endothelial, inducible and neuronal) have been identified in tubular and vascular capillaries of kidney [23, 24].…”

Predicted effects of nitric oxide and superoxide on the vasoactivity of the afferent arteriole

“…The affinities for Ca 2ϩ (K M,PMCA Ca ) and for cGMP (K M,cGMP PMCA ) are taken as 0.170 M (18) and 1.0 M (10), respectively. To obtain a better fit with afferent arteriole data, we assume a smaller dependence of the PMCA current on cGMP levels than in our descending vasa recta model (10).…”

“…The kinetics of NO and O 2 Ϫ formation, diffusion, and reaction are modeled as in our previous study of NO-induced vasodilation of descending vasa recta (10). We assume that the only source of NO is the endothelium.…”

Impact of nitric oxide-mediated vasodilation on outer medullary NaCl transport and oxygenation

“…The DVR endothelium is surrounded by pericytes, vascular smooth muscle cells that impart vasocontractile properties to the vessels. The vasodilatory effects of NO appear to be mostly mediated by the cGMP/PKG pathway, which acts to reduce intracellular Ca 2ϩ and the proportion of phosphorylated myosin light chains within pericytes (13). Moreover, vascular diameter is regulated by many other vasoactive agents, such as prostaglandins and endothelins.…”