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. Author manuscript; available in PMC: 2017 Nov 1.
Published in final edited form as: Hypertension. 2016 Aug 29;68(5):1236–1244. doi: 10.1161/HYPERTENSIONAHA.116.07954

Regular exercise reduces endothelial cortical stiffness in Western diet-fed female mice

Jaume Padilla 1,2,3,*, Francisco I Ramirez-Perez 2,4,*, Javad Habibi 6,*, Brian Bostick 5, Annayya R Aroor 6, Melvin R Hayden 6, Guanghong Jia 6, Mona Garro 6, Vincent G DeMarco 6, Camila Manrique 6, Frank W Booth 1,9, Luis A Martinez-Lemus 2,4,7, James R Sowers 2,6,7,8
PMCID: PMC5063712  NIHMSID: NIHMS808832  PMID: 27572153

Abstract

We recently showed that Western diet (WD)-induced obesity and insulin resistance promotes endothelial cortical stiffness in young female mice. Herein, we tested the hypothesis that regular aerobic exercise would attenuate the development of endothelial and whole artery stiffness in female WD-fed mice. Four-week old C57BL/6 mice were randomized into sedentary (i.e., caged confined, n=6) or regular exercise (i.e., access to running wheels, n=7) conditions for 16 weeks. Exercise training improved glucose tolerance in the absence of changes in body weight and body composition. Compared to sedentary mice, exercise-trained mice exhibited reduced endothelial cortical stiffness in aortic explants (sedentary: 11.9±1.7 kPa vs. exercise: 5.5±1.0 kPa; p<0.05), as assessed by atomic force microscopy. This effect of exercise was not accompanied by changes in aortic pulse wave velocity (p>0.05), an in vivo measure of aortic stiffness. In comparison, exercise reduced femoral artery stiffness in isolated pressurized arteries and led to an increase in femoral internal artery diameter and wall cross-sectional area (p<0.05), indicative of outward hypertrophic remodeling. These effects of exercise were associated with an increase in femoral artery elastin content and increased number of fenestrae in the internal elastic lamina (p<0.05). Collectively, these data demonstrate for the first time that the aortic endothelium is highly plastic and thus amenable to reductions in stiffness with regular aerobic exercise in the absence of changes in in vivo whole aortic stiffness. Comparatively, the same level of exercise caused de-stiffening effects in peripheral muscular arteries such as the femoral artery that perfuse the working limbs.

Keywords: Arterial stiffness, physical activity, obesity, animal models of Human Disease, Vascular Biology

INTRODUCTION

Stiffening of the vasculature is a hallmark characteristic of obesity and diabetes1–4 as well as the aging process;5 furthermore, arterial stiffness is an independent predictor of morbidity and mortality related to cardiovascular, cerebrovascular, and chronic kidney disease.6–10 This impact of obesity and metabolic disease on arterial stiffening is particularly pronounced in women,11 which may explain why insulin-resistant and obese women are at higher risk for developing cardiovascular disease (CVD) than men.12–14 Consequently, identification of strategies that attenuate obesity and insulin resistance-mediated vascular stiffness in females is of paramount importance.

Arterial stiffness can be affected by changes in endothelial and smooth muscle cell structure and function and by alterations in the extracellular matrix.15 Using the sensitive atomic force microscopy (AFM) methodology, our group recently demonstrated that young obese, insulin-resistant, female mice fed a Western diet (WD) exhibit increased stiffness of the endothelium from aortic explants, and that oxidative stress/inflammation is likely implicated.16,17 Endothelial stiffening reduces flow-mediated endothelial nitric oxide (NO) synthase activation and NO bioavailability, and increases endothelial cell adhesion and permeability,18–22 thus representing a cause and distinguishing feature of vascular dysfunction. In view of evidence that diminished shear forces may contribute to the induction of endothelial stiffness,22,23 we posited that aerobic exercise-induced increases in blood flow and consequent increases in shear stress would lead to a decrease in endothelial stiffness. In this regard, shear stress has been proposed as a primary physiological signal by which exercise produces favorable vascular adaptations.24 However, to date, the effect of exercise on endothelial stiffness associated with diet-induced obesity has not been examined. Herein, using a female mouse model of WD-induced obesity, insulin resistance and cardiovascular stiffness,16,17,25–27 we tested the hypothesis that regular volitional exercise would reduce stiffness in the aortic endothelium, as assessed by AFM in aortic explants, as well as reduce in vivo aortic stiffness, as assessed by pulse wave velocity (PWV). Furthermore, we hypothesized that changes in aortic stiffness produced by exercise would be accompanied by a reduction in oxidative stress. Lastly, we reasoned that exercise-induced de-stiffening effects would be highly pronounced in the femoral artery, a muscular artery highly susceptible to WD-induced stiffness27 and exposed to high blood flow and associated increased shear stress during exercise.

METHODS

Four-week old C57BL/6 mice were fed a WD high in fat and sugars and randomized into sedentary (i.e., caged confined, n=6) or regular exercise (i.e., access to running wheels, n=7) conditions for 16 weeks. For detailed description of procedures, see Methods in the online only Supplement.

Statistical analysis

All data are presented as mean ± standard error (SE). Independent t-test was used to compare sedentary versus exercise-trained mice on all dependent variables. For all statistical tests, the alpha level was set at 0.05. Statistical analyses were performed with SPSS V23.0. Sample size calculation was performed and determined that 5 animals per group was sufficient to detect between-group differences in aortic endothelial stiffness, a primary end-point of the study. A type 1 error size of 0.05 and power of 0.80 was used.

RESULTS

Exercising female mice ran an average of 7.1±1.5 km/day over the 16 week period (Figure S1A) and consumed a greater amount of calories compared to sedentary females (Figure S1B; p=0.005). At the end of the study period, body weights (p=0.883) and percent body fat (p=0.362) were not different between both groups of mice (Figure S1C and D), neither were visceral fat pad weights (p=0.475, data not shown). Exercise-trained mice exhibited greater glucose tolerance (Figure S1E) relative to sedentary mice (p=0.03).

As shown in Figure 1, aortic endothelial stiffness (panel A; p=0.008), but not aortic PWV (panel B; p=0.242), was attenuated in exercise-trained mice, compared to sedentary mice. Heart rates, as assessed via EKG during the PWV measurements, were not different between groups (sedentary: 400±8; exercise: 386±15 beats per minute; p=0.443). Statistical correction of PWV for heart rate using covariate analysis did not alter the interpretation of the findings. Observation of transmission electron microscopy (TEM) images of aortic samples revealed an increase in endothelial cell length in exercise-trained mice, suggestive of reduced endothelial cell contractility (Figure 1C–E).

Figure 1. Ex vivo aortic endothelial stiffness, in vivo aortic PWV, and aortic endothelial cell length in sedentary (SED) and exercise trained (EX) female mice fed a WD.

Figure 1

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(A) Endothelial stiffness as assessed by AFM. (B) Aortic PWV. (C–E) Aortic endothelial cell length. Representative TEM photographs of aortic samples demonstrating aortic endothelial cell contraction (8–10µm) in sedentary female mice fed a WD was corrected with regular exercise (18–20µm). Arrows denote endothelial cell-cell junctions and dashed lines indicate the distance between cell-cell junctions in micrometers. Magnification ×800; bar = 2 µm. ECM = extracellular matrix; IEL = internal elastic lamina; EL= tunica media elastic lamina; N = endothelial cell nucleus. Data are expressed as means ± SE. NS, non-significant (p>0.05). N=6–7/group in panels A and B. Panel C illustrates the mean (± SE) endothelial cell length of 12 cells per group.

Figure 2 displays findings from immunohistochemical experiments performed in aortic samples demonstrating an exercise-related decrease in 3-nitrotyrosine in the endothelium and media (panel A), decrease in transforming growth factor (TGF)β staining in the endothelium, media, and adventitia (panel B), and decrease in connective tissue growth factor (CTGF) staining in the endothelium (panel C) (all p<0.05). The effects of exercise on 3-nitrotyrosine in whole aorta samples using a Western slot blot are presented in Figure S2. In addition, Figure 3 summarizes the effects of exercise on expression of fibronectin (panel A) and collagen-1 (panel B) in the media and adventitia of aortic wall. Modest effects of exercise on collagen-1 were noted in the media (p=0.05) and no significant effects were found in the adventitia. Periaortic fibrosis, as assessed by Picro Sirius Red (PSR) staining, and medial wall thickness were not affected by regular exercise (p>0.05; Figure S3). The periaortic/adventitial area stained with PRS was also not different between groups (p=0.488).

Figure 2. Immunohistochemical staining of 3-nitrotyrosine (A), TGFβ (B) and CTGF (C) in aortic samples from sedentary (SED) and exercise trained (EX) female mice fed a WD.

Figure 2

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Data are expressed as means ± SE. NS, non-significant (p>0.05); EC, endothelial cell layer; M, media; AD, adventitia, F, fat. Bar =50 µm. N=5–6/group.

Figure 3. Immunohistochemical staining of fibronectin (A) and collagen-1 (B) in aortic samples from sedentary (SED) and exercise trained (EX) female mice fed a WD.

Figure 3

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Data are expressed as means ± SE. AD, adventitia; M, media. Bar =50 µm. N=5–6/group.

As illustrated in Figure 4, exercise trained females exhibited a significant (p<0.05) increase in femoral artery internal (panel A) and external (panel B) diameters, significant changes in circumferential stress at specific intraluminal pressures (panel C), increase in wall cross-sectional area (panel D), decrease in incremental modulus of elasticity (panel E), increase in cross-sectional compliance (panel F), increase in wall to lumen ratio (Figure S4A), and increase in mean wall thickness (Figure S4B). Femoral artery responses to 80 mM KCl were not different between groups (data not shown). Confocal and multi-photon fluorescence microscopy was used to assess the composition of the femoral artery wall and these data are presented in Figure 5. Femoral arteries from exercise trained females exhibited greater elastin content than sedentary mice (Figure 5E; p=0.022), but no statistical differences were noted for F-actin, nuclei, and collagen (all p>0.05). The number of fenestrae and area per fenestra in the internal elastic lamina were also evaluated in the femoral arteries. As shown in Figure 6, exercise-trained mice exhibited an increase in the number of femoral artery fenestrae (panel C; p=0.006) and the mean area occupied by each fenestra (panel D; p=0.048). In addition, the modulus of elasticity specific for the internal elastic lamina at the pressure in which the arteries were fixed (70 mmHg) normalized as a function of the percolation (E/E0)56 of its fenestrae was reduced with exercise (Figure 6E; p=0.0006).

Figure 4. Structural properties of femoral arteries kept under passive conditions at different intravascular pressures from sedentary (SED) and exercise trained (EX) female mice fed a WD.

Figure 4

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(A–B) Pressure-diameter curves. (C) Strain-stress relationship curves. (D) Cross sectional area of the vascular wall. (E) Incremental modulus of elasticity. (F) Cross-sectional compliance. Data are expressed as means ± SE. *Denote data points that were statistically significant (p<0.05) between SED and EX. For Panel C, * denotes significant difference (p<0.05) in circumferential stress between SED and EX for the last 5 points which correspond to measurements taken from 40 to 120 mmHg. No significant differences (p>0.05) in strain were found between SED and EX. N=5–7/group.

Figure 5. Morphological characteristics of femoral arteries from sedentary (SED) and exercise trained (EX) female mice fed a WD.

Figure 5

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(A) Representative confocal images of femoral arteries showing F-actin, nuclei, and collagen. (B) Femoral artery F-actin content. (C) Vascular smooth muscle cell number, assessed by the volume of nuclei contained within the medial layer of femoral arteries. (D) Femoral artery collagen content. (E) Femoral artery elastin content. All volumes are expressed as number of voxels. (F) Representative confocal images of femoral arteries showing elastin. Data are expressed as means ± SE. NS, non-significant (p>0.05). N=5/group.

Figure 6. Internal elastic lamina characteristics of femoral arteries from sedentary (SED) and exercise trained (EX) female mice fed a WD.

Figure 6

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(A–B) Representative confocal images of the internal elastic lamina in femoral arteries. (C–D) Number of fenestrae and area per fenestra (pixels) within the internal elastic lamina in femoral arteries. (E) Modulus of elasticity normalized as a function of the percolation of the internal elastic lamina and its fenestrae. Data are expressed as means ± SE. N=4–5/group.

DISCUSSION

The primary and novel finding of the present investigation is that regular aerobic exercise reduces endothelial cortical stiffness and contractility in young female WD-fed obese mice. Decreased endothelial stiffness in aortic explants of exercising females was not accompanied by a reduction in aortic PWV, suggesting that endothelial effects of regular exercise may precede detectable changes in whole aortic stiffness. Notably, exercise markedly reduced stiffness in the femoral artery, thus supporting the notion that the initial de-stiffening effects of exercise primarily manifest in peripheral muscular arteries perfusing the working limbs. These findings are of considerable translational importance given that obesity and insulin resistance are strongly associated with cardiovascular stiffness, especially in females.16,25–27

The favorable effects of regular exercise in prevention and treatment of CVD are not exclusively mediated by the lessening of systemic conventional risk factors.28–31 Existing data indicate that at least 40% of the CVD risk reduction related to exercise cannot be accounted for by the modification of established or emerging CVD risk factors.28–31 Considering this gap in our understanding of risk factors involved in promoting CVD, it is conceivable that exercise exerts direct protective effects on the arterial wall, a concept recently coined as vascular conditioning.29,31,32 Our finding that volitional aerobic exercise attenuated aortic endothelial and femoral artery stiffness, without significant changes in body weight or body composition supports the idea that the impact of exercise on the vasculature is largely independent of changes in adiposity in the setting of consumption of a WD.

During exercise, the metabolic demands of contracting muscle cause an increase in cardiac output and blood flow to the working muscles, thus resulting in marked increases in vascular shear stress in arteries supplying blood to the active muscles.33 Increased shear stress is one likely physiological signal for vascular adaptations to regular exercise.24 The concept that vascular adaptations are mediated by shear stress-dependent mechanisms is indeed supported by cell and organ culture34–39 as well as in vivo animal40,41 and human42–44 experiments. The fact that arterial regions exposed to unidirectional and moderate/high levels of shear stress exhibit lower endothelial stiffness also supports the idea that shear forces may contribute to the regulation of endothelial stiffness.22,23 Further, there is emerging evidence that endothelial cortical stiffness and glycocalyx disarray leads to diminished eNOS activation.16,18–22,45,46 The molecular mechanisms by which exercise-induced shear stress may reduce endothelial rigidity are not fully elucidated. However, reduced stiffness leads to shear stress-mediated increases in eNOS-derived NO, which, in turn, feeds back to reduced endothelial cortical stiffness.47,48 Another mechanism by which exercise restores vascular NO bioavailability in the setting of obesity and insulin resistance may be related to the reduction in oxidative stress, as superoxide radicals react with NO to form peroxynitrite.49,50 In this regard, we found that exercise reduced 3-nitrotyrosine, a marker of peroxynitrite, in the endothelium and media. The finding that exercise reduces vascular oxidative stress and arterial stiffness has also been shown in rodent models of aging,51 and therapies that scavenge superoxide radicals (e.g., tempol) reverse aortic stiffening induced by aging.52 Accordingly, it is possible that the exercise-induced reduction in aortic endothelial stiffness is in part mediated by a reduction in reactive oxygen species; however, more research is needed to test this novel hypothesis. In addition, we also found that exercise reduced endothelial expression of TGFβ and CTGF, two profibrotic cytokines. Increased expression of TGFβ and CTGF has been implicated in the increase in vascular collagen and fibronectin synthesis and accompanying increases in fibrosis/stiffness in rodent models of aging, diet-induced obesity, and hypertension.27,53–56 To this point, we found that exercise was associated with a reduction in aortic tissue fibronectin and collagen-1 (stiff collagen form) in the adventitia and media, respectively. However, despite this reduction in expression of TGFβ, CTGF, fibronectin and collagen-1, we did not detect significant changes in periaortic fibrosis, as assessed with PRS staining, which may explain the lack of exercise effects on aortic PWV, an in vivo marker of aortic stiffness. Taken together, these data provide evidence that regular exercise produces de-stiffening effects in aortic endothelium despite no evident changes in whole aortic stiffness, thus supporting the plasticity of endothelial cells in response to exercise training.

In this regard, we also noted dysmorphic ultrastructural abnormalities in the aortic endothelial cell layer of sedentary WD-fed mice. In particular, examination of TEM images of aortic samples from sedentary WD-fed mice revealed evidence of endothelial cell contraction which was not apparent in exercise trained mice also fed a WD. To our knowledge, this is the first time this observation is reported. It is reasonable to speculate that this phenotypic effect of aerobic exercise may be mediated by the increases in shear stress and contribute to the reduction in endothelial stiffness. However, more research is needed to elucidate the precise mechanism through which exercise and associated shear stress modulate endothelial cell contractility.

The lack of exercise effect on aortic PWV is in stark contrast with the pronounced de-stiffening effects of exercise observed in the femoral artery. Specifically, in pressurized femoral arteries, we found that exercise-trained mice exhibited reduced moduli of elasticity and increased cross-sectional compliance, both indicative of decreased stiffness, thus demonstrating that regular exercise is effective at reversing femoral artery stiffness previously shown to be caused by WD.27 Given that in our former study27 we found that WD-induced femoral artery stiffness was associated with decreased F-actin to nuclei and elastin to collagen ratios as assessed using confocal and multi-photon fluorescence microscopy, the composition of the femoral artery wall in response to exercise was also assessed in the present study. Although collagen content of the femoral arteries was not affected by exercise, trained mice exhibited greater femoral artery elastin content, which may have contributed to the decreased stiffness in this artery. Furthermore, we report for the first time that regular exercise increased the number of fenestrae and area occupied by fenestrae in the internal elastic lamina of the femoral artery. Our novel finding that regular exercise increased the number of fenestrae in the internal elastic lamina of femoral arteries is of relevance in light of prior findings by our group and others demonstrating that high-fat diet decreases the number of fenestrae in the internal elastic lamina of femoral27 and mesenteric57,58 arteries of mice. These changes in fenestration of the internal elastic lamina may be associated with changes in the elastic properties of the vessels as well as with the communication between endothelial and vascular smooth muscle cells within the vascular wall.57,59,60 Fenestrae play a vital role in the capacity of the internal elastic lamina to tolerate circumferential wall stress, which is profoundly increased during aerobic exercise. Of note, data in rabbits indicate that area of fenestrae in the internal elastic lamina of carotid arteries is reduced following exposure to chronic low blood flow and increased following exposure to chronic high blood flow-induced shear stress.61 These findings, combined with our new observation that regular exercise increases fenestrae in the femoral artery, suggest that hemodynamic forces, and shear stress in particular, may play a critical role in the regulation of internal elastic lamina ultrastructure and stability.

The finding that aerobic exercise did not affect aortic stiffness but markedly reduced stiffness in femoral arteries is consistent with findings from human studies.62 Indeed, data from a recent meta-analysis indicated that aerobic exercise significantly improved PWV and that this effect of exercise tended to be greater in peripheral arteries than in the aorta.62 Prior randomized controlled trials have also concluded that exercise training does not reduce aortic PWV in patients with highly stiffened arteries.63,64 Whether these artery-specific effects of exercise are dependent on the structural properties of the vessel (muscular arteries such as femoral artery versus elastic/capacitance arteries such as aorta) or the distinct hemodynamic forces to which the arteries are subjected during exercise requires further investigation. Regardless, our data provide further support to the notion that the vascular effects of exercise are heterogeneous throughout the arterial tree.65–67

Another prominent observation of the present investigation was that regular exercise increased femoral artery (internal and external) diameter and wall cross-sectional area, indicative of outward hypertrophic remodeling. This vascular remodeling likely serves to withstand the increases in intraluminal pressure and blood flow imposed by exercise and it is reminiscent of the chronic exercise-induced eccentric left ventricular hypertrophy found in humans.68 A proposed mechanism responsible for exercise-induced arterial enlargement is increased shear stress-mediated endothelium-derived NO. This notion is consistent with a prior study69 that employed an arteriovenous fistula between the left common carotid artery (CCA) and the external jugular vein in rats chronically treated with or without NOS synthase inhibitor (L-NAME) in drinking water. In this study paradigm, it was found that increased blood flow-induced CCA enlargement was attenuated with NOS inhibition, thus demonstrating that NO plays a role in the increase of vessel caliber in response to chronic shear.69 Eloquent data supporting the role of blood flow-induced shear stress in modulating arterial diameter in the context of exercise are also available from human studies.42,70 Also, consistent with our findings in obese female mice, studies in overweight women demonstrate that aerobic exercise increases femoral artery diameter without changes in aortic PWV or adiposity;71 thus further emphasizing the translational impact of our model.

Several considerations for the overall interpretation of the current findings are warranted. First, aortic PWV was assessed for determination of in vivo aortic stiffness, whereas stiffness in the femoral artery was assessed ex vivo in pressurized arteries. Although unlikely, it is possible that the contrasting effects of exercise in the aorta and femoral artery are in part attributable to differences in measurement techniques (e.g., in vivo vs. ex vivo). In this regard, it should be emphasized that not all molecular and ultrastructural assays performed in both regions of the vasculature were matched and this presents a limitation of the study. It should be noted that enhanced vascular expression of eNOS and NO bioavailability with exercise and shear stress has been well described in the animal and human literature;43,72–74 however, these measurements were not performed in the present investigation. Furthermore, although our group has previously shown cardiovascular stiffness induced by WD is not accompanied by changes in blood pressure,16 we did not measure blood pressure in the present study. Therefore, we cannot exclude the possibility that the vascular effects of exercise observed here were in part mediated by a reduction in blood pressure. Along these lines, it is also possible that improvements in glycemic control, as noted in the present study, contributed to vascular adaptations in response to exercise that are independent of effects of shear stress. In this regard, the link between glycemic dysregulation, oxidative stress, and arterial stiffness is well documented.75–78

In conclusion, the present study revealed for the first time that regular aerobic exercise attenuates endothelial cortical stiffness in aortic explants from female mice fed a WD, an effect that was accompanied by a reduction in endothelial contractility and decrease in endothelial nitrotyrosine, TGFβ and CTFG. These effects of exercise were not accompanied by a lowering of periaortic fibrosis and in vivo aortic stiffness as assessed by PWV. Whether greater intensity or duration of exercise (e.g., 32 weeks) would produce different results needs further investigation. Notably, de-stiffening and structural remodeling effects of exercise were prominently noted in the femoral artery, and these findings were paralleled by the novel observations that exercise increased femoral artery elastin content as well as the number of fenestrae and area per fenestra in the internal elastic lamina. These vascular adaptations to exercise occurred concurrently with improvements in glucose tolerance but in the absence of significant changes in body weight and adiposity.

Supplementary Material

Supplemental Methods and Results

Perspectives.

These data in female mice demonstrate that aortic endothelium is highly plastic and thus amenable to reductions in stiffness with regular aerobic exercise despite no changes in whole aortic stiffness as determined in vivo by PWV. Thus, the relevance of exercise-related de-stiffening is manifested in peripheral muscular arteries perfusing the working limbs, but not in the aortic wall as a whole. Findings from this investigation are of translational importance because obesity and insulin resistance are strongly linked to cardiovascular stiffness, especially in women. The vascular de-stiffening effects of aerobic exercise reported herein may contribute to a reduction in CVD and peripheral artery disease in particular.

NOVELTY AND SIGNIFICANCE.

  1. What is New? These data demonstrate for the first time that regular aerobic exercise reduces aortic endothelial stiffness and this effect occurs in the absence of changes in aortic pulse wave velocity, a marker of whole aortic stiffness.

  2. What is Relevant? The impact of obesity and metabolic disease on arterial stiffening is particularly pronounced in women, which may explain why insulin-resistant women are at higher risk for developing cardiovascular disease than men. Consequently, identification of strategies that attenuate obesity and insulin resistance-mediated vascular stiffness in females is of paramount importance.

  3. Summary: We found that 16 weeks of wheel running in C57BL/6 female mice fed a Western diet reduces aortic endothelial cell contractility and stiffness despite no changes in aortic pulse wave velocity. De-stiffening and structural remodeling effects of exercise were prominently noted in the femoral artery, and these findings were paralleled by the observations that exercise increased femoral artery elastin content as well as the number of fenestrae in the internal elastic lamina. These vascular adaptations to exercise occurred concurrently with improvements in glucose tolerance but in the absence of significant changes in body weight and adiposity.

Acknowledgments

We gratefully acknowledge Brenda Hunter for editorial assistance. In addition, we acknowledge the Electron Microscopic Core Center at the University of Missouri for sample preparation and assistance.

SOURCES OF FUNDING

This work was supported by grants from the American Heart Association (13POST16250010 to B.B.), the National Institutes of Health (HL-125503 and DK-105368 to J.P.; 1K08HL129074-01 to C.M.; HL-088105 to L.A.M-L.; HL-073101 and HL-107910 to J.R.S.) and the Department of Veterans Affairs Biomedical Laboratory Research and Development (0018 to J.R.S.). This work was also supported with resources and the use of facilities at the Harry S. Truman Memorial Veterans Hospital in Columbia, MO.

Footnotes

CONFLICTS OF INTEREST/DISCLOSURES

None

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