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Atherosclerosis is responsible for the death of thousands of Americans each year. The carotid constriction model of plaque development has recently been presented as a model for unstable plaque formation in mice. In this study we 1) validate ultrasound biomicroscopy (UBM) for the determination of carotid plaque size, percent stenosis, and plaque development in live animals, 2) determine the sensitivity of UBM in detecting changes in blood flow induced by carotid constriction and 3) test whether plaque formation can be predicted from blood flow parameters measured by UBM. Carotid plaques were induced by surgical constriction in Apo E2/2 mice. Arteries were imaged bi-weekly by UBM, at which time PW-Doppler measurements of proximal blood flow, as well as plaque length and percent stenosis were determined. Histology was performed 9 weeks post surgery. When compared to whole mount post-mortem measurements, UBM accurately reported carotid plaque length. Percent stenosis, based on transverse B-mode UBM measurements, correlated well with that calculated from histological sections. PW-Doppler revealed that constriction reduced maximum systolic velocity (vmax) and duration of the systolic velocity peak (ts/tt). Pre-plaque (2 week post-surgery) PW-Doppler parameters (vmax and ts/tt) were correlated with plaque length at 9 weeks, and were predictive of plaque formation. Correlation of initiating PW-Doppler parameters (vmax and ts/tt) with resulting plaque length established the degree of flow disturbance required for subsequent plaque development and demonstrated its power for predicting plaque development. [ABSTRACT FROM AUTHOR]

Stroke is a leading cause of death in the United States. As ∼60% of strokes result from carotid plaque rupture, elucidating the mechanisms that underlie vulnerability is critical for therapeutic intervention. We tested the hypothesis that stable and vulnerable human plaques differentially express genes associated with matrix degradation. Examination established that femoral, and the distal region of carotid, plaques were histologically stable while the proximal carotid plaque regions were vulnerable. Quantitative RT-PCR was used to compare expression of 22 genes among these tissues. Distal carotid and femoral gene expression was not significantly different, permitting the distal carotid segments to be used as a paired control for their corresponding proximal regions. Analysis of the paired plaques revealed differences in 16 genes that impact plaque stability: matrix metalloproteinases (MMP, higher in vulnerable), MMP modulators (inhibitors: lower, activators: higher in vulnerable), activating Fc receptors (Fcγ, higher in vulnerable) and Fcγ signaling molecules (higher in vulnerable). Surprisingly, the relative expression of smooth muscle cell and macrophage markers in the three plaque types was not significantly different, suggesting that macrophage distribution and/or activation state correlates with (in)stability. Immunohistochemistry revealed that macrophages and smooth muscle cells localize to distinct and non-overlapping regions in all plaques. MMP protein localized to macrophage-rich regions. In vitro, treatment of macrophages with immune complexes, but not oxidized low density lipoprotein, C-reactive protein, or TNF-α, induced a gene expression profile similar to that of the vulnerable plaques. That ligation of Fcγ recapitulates the pattern of gene expression in vulnerable plaques suggests that the Fcγ → R macrophage activation pathway may play a greater role in human plaque vulnerability than previously appreciated. [ABSTRACT FROM AUTHOR]

Studies blood circulation and glucose uptake in denervated, insulin-resistant muscles. Influence of muscle fiber population on muscle blood flow; Basal and insulin-stimulated 2-deoxy-D-glucose uptake in fast-twitch and slow-twitch muscles.

Microdialysis sampling is a method that has promise for collection of important signaling proteins such as cytokines that are involved in every aspect of the immune response. The objective of this study was to determine the role of membrane and tissue alterations on the reduction of interleukin-6 (IL-6) relative recovery of microdialysis probes implanted for 3 and 7 days versus probes implanted on day 0 (acute implant or control probe). Lipopolysaccharide (LPS), a bacterial endotoxin, was used to elicit IL-6 production in the animals. Within the same animal, the recovery of IL-6 through control probes implanted the day of sample collection was compared to the 3- or 7-day implanted probes. Two hours post-LPS administration, the IL-6 concentrations obtained from either the 3-day or 7-day implanted probe were reduced by more than 8-fold when compared to the control probe. The IL-6 concentrations obtained for the 3-day versus control probes 2-h post-LPS injection were 730 ± 310 and 6440 ± 1550 pg/mL (mean ± SD, n = 3), respectively. For the 7-day implant, the IL-6 concentration in the dialysis probe obtained at 2-h post-LPS injection was 990 ± 590 versus 5520 ± 1430 pg/mL (mean ± SD, n = 3) for the control. In vitro recovery experiments and scanning electron microscopy images combined with the in vivo data suggest that the decreased IL-6 content in the dialysate was caused principally by tissue alterations or tissue encapsulation rather than membrane blockage with biological components (membrane biofouling). [ABSTRACT FROM AUTHOR]

Investigates whether Fcgamma-receptor signaling augments the lipopolysaccharide (LPS)-stimulated increase in serum tumor necrosis factor-alpha levels. Effect of immunoglobulin G-coated erythrocytes on LPS-stimulated serum TNF-alpha levels in mice; Role of the Fcgamma-receptor in the priming of TNF-alpha secretion.