Nitric oxide signaling in the microcirculation

Abstract

Several apparent paradoxes are evident when one compares mathematical predictions from models of nitric oxide (NO) diffusion and convection in vasculature structures with experimental measurements of NO (or related metabolites) in animal and human studies. Values for NO predicted from mathematical models are generally much lower than in vivo NO values reported in the literature for experiments, specifically with NO microelectrodes positioned at perivascular locations next to different sizes of blood vessels in the microcirculation and NO electrodes inserted into a wide range of tissues supplied by the microcirculation of each specific organ system under investigation. There continues to be uncertainty about the roles of NO scavenging by hemoglobin versus a storage function that may conserve NO, and other signaling targets for NO need to be considered. This review describes model predictions and relevant experimental data with respect to several signaling pathways in the microcirculation that involve NO.

FIGURE 1

Calcium fluorescence data from Hong et al. obtained with bovine aortic endothelial cells (BAECs) (A, B) and rat adrenomedulary endothelial cells (ECs) derived from capillary endothelium (C, D). Synchronous Ca²⁺ responses with similar shear stress–dependent peak values were observed with BAECs, but heterogeneous Ca²⁺ responses were observed (C) with rat adrenomedulary ECs, although some cells had a synchronized response delayed in time after an increase in shear stress (D). Modified from Figs. 1 and 2 in Hong et al., with permission from the American Journal of Physiology.

FIGURE 2

Computer simulations conducted by Comerford et al. for spatial distributions of endothelial nitric oxide synthase (eNOS) protein in vascular bifurcations and bends. Regions with low wall shear stress (WSS; calculated from a fluid dynamics model) are associated with low eNOS expression and based on a functional relationship determined for eNOS with WSS from experimental studies by Cheng et al.^, Modified from Figs. 7 and 11 in Comerford et al., with permission from the Journal of Biomechanical Engineering.

FIGURE 3

In vivo studies of endothelium-dependent propagated vascular responses to local electrical stimulation in the mouse cremaster microcirculation by Figueroa et al. Removal of endothelium at the simulation site by air embolism greatly attenuates downstream responses (A); an inhibitor of nitric oxide (NO) production partially attenuates propagated responses (B); and propagated responses are smaller in endothelial NO synthase knockout mice compared with wild-type mice (C). Modified from Figs. 2 and 7 in Figueroa et al., with permission from the American Journal of Physiology.

FIGURE 4

Computational model of 3-dimensional microcirculatory network by Chen predicting nitric oxide (NO) distributions (A) with different blood flow rates. Distribution of wall shear stress in 2 branching arterioles (B) and redistribution of red blood cells with branching have an impact on the NO distribution (C) around these branches. Reprinted from Chen.

FIGURE 5

Mapping of perivascular nitric oxide (NO) in superfused rat mesentery and small intestine conducted in our laboratory (unpublished) using Nafion-coated recessed NO microelectrodes (top panel). Examples of experimental vessel diameter measurements and NO measurements also are shown (bottom graphs). For venule and arteriole measurements, the NO microelectrode initially was positioned far from the vessel (zero reading), then moved to touch the outer surface of the vessel gently (perivascular NO value). The microelectrode image interfered with video diameter measurements when it was near the vessel (for clarity, the diameter signal is removed just before the tip touches the vessel). For the capillary-perfused site, the NO microelectrode was initially far from the tissue surface, then was moved to the surface and back out into the superfusion bath. The NO microelectrode current was converted to concentration based on calibrations at known NO concentrations.

FIGURE 6

In vivo study by Tsai et al. using nitric oxide (NO) microelectrodes to measure perivascular and tissue (T) NO in the dorsal skin chamber of unanesthetized hamsters for control animals and animals receiving isovolemic hemodilution with either low- or high-viscosity solutions. *P < 0.05. **P < 0.01. ***P < 0.001. A, arteriole; NS, not significant; V, venule. Modified from Fig. 5 in Tsai et al., with permission from the American Journal of Physiology.

FIGURE 7

Differences in effects of nitric oxide (NO) on inhibition of O₂ consumption as modeled by Buerk and Hall and Garthwaite. The model by Hall and Garthwaite has a stronger dependence of apparent K_m on NO (A), with greater inhibition of O₂ consumption by NO (B) than that predicted from model by Buerk (C).

FIGURE 8

In vitro measurements by Ledo et al. of changes in nitric oxide (NO) and tissue O₂ in rat hippocampus slice following pressure injection of different concentrations of N-methyl-D-aspartic acid (A) provides evidence for inhibition of O₂ consumption by NO because tissue O₂ increases with higher NO (B). Modified from Figs. 1 and 2 in Ledo et al.,with permission from Free Radical Biology and Medicine.