Differential changes in vascular mRNA levels between rat iliac and renal arteries produced by cessation of voluntary running.

Early vascular changes at the molecular level caused by adoption of a sedentary lifestyle are incompletely characterized. Herein, we employed the rodent wheel-lock model to identify mRNAs in the arterial wall that are responsive to the acute transition from higher to lower levels of daily physical activity. Specifically, we evaluated whether short-term cessation of voluntary wheel running alters vascular mRNA levels in rat conduit arteries previously reported to have marked increases (i.e. iliac artery) versus marked decreases (i.e. renal artery) in blood flow during running. We used young female Wistar rats with free access to voluntary running wheels. Following 23 days of voluntary running (average distance of ∼15 km per night; ∼4.4 h per night), rats in one group were rapidly transitioned to a sedentary state by locking the wheels for 7 days (n = 9; wheel-lock 7 day rats) or remained active in a second group for an additional 7 days (n = 9; wheel-lock 0 day rats). Real-time PCR was conducted on total RNA isolated from iliac and renal arteries to evaluate expression of 25 pro-atherogenic and anti-atherogenic genes. Compared with the iliac arteries of wheel-lock 0 day rats, iliac arteries of wheel-lock 7 day rats exhibited increased expression of TNFR1 (+19%), ET1 (+59%) and LOX-1 (+31%; all P < 0.05). Moreover, compared with renal arteries of wheel-lock 0 day rats, renal arteries of wheel-lock 7 day rats exhibited decreased expression of ETb (-23%), p47phox (-32%) and p67phox (-19%; all P < 0.05). These data demonstrate that cessation of voluntary wheel running for 7 days produces modest, but differential changes in mRNA levels between the iliac and renal arteries of healthy rats. This heterogeneous influence of short-term physical inactivity could be attributed to the distinct alteration in haemodynamic forces between arteries.

Vascular effects of exercise: endothelial adaptations beyond active muscle beds.

Endothelial adaptations to exercise training are not exclusively conferred within the active muscle beds. Herein, we summarize key studies that have evaluated the impact of chronic exercise on the endothelium of vasculatures perfusing nonworking skeletal muscle, brain, viscera, and skin, concluding with discussion of potential mechanisms driving these endothelial adaptations.

Impact of a single session of intermittent pneumatic leg compressions on skeletal muscle and isolated artery gene expression in rats.

Intermittent pneumatic leg compressions (IPC) have proven to be an effective noninvasive approach for treatment of patients with claudication, but the mechanisms underlying the clinical benefits remain elusive. In the present study, a rodent model of claudication produced by bilateral ligation of the femoral artery was used to investigate the acute impact of a single session of IPC (150 min) on hemodynamics, skeletal muscle (tibialis anterior), and isolated collateral artery (perforating artery) expression of a subset of genes associated with inflammation and vascular remodeling. In addition, the effect of compression frequency (15 vs. 3 compressions/min) on the expression of these factors was studied. In ligated animals, IPC evoked an increase of monocyte chemoattractant protein-1 (MCP-1) and cytokine-induced neutrophil chemoattractant 1 (CXCL1) mRNA (P < 0.01) and immunostaining (P < 0.05), as well as a minor increase in VEGF immunostaining in the muscle endomysium 150 min postintervention. Further, collateral arteries from these animals showed an increased expression of MCP-1 (approximately twofold, P = 0.02). These effects were most evident in the group exposed to the high-frequency protocol (15 compressions/min). In contrast, IPC in sham-operated control animals evoked a modest initial upregulation of VEGF (P = 0.01), MCP-1 (P = 0.02), and CXCL1 (P = 0.03) mRNA in the muscle without concomitant changes in protein levels. No changes in gene expression were observed in arteries isolated from sham animals. In conclusion, IPC acutely up-regulates the expression of important factors involved in vascular remodeling in the compressed muscle and collateral arteries in a model of hindlimb ischemia. These effects appear to be dependent on the compression frequency, such that a high compression frequency (15 compressions/min) evokes more consistent and robust effects compared with the frequency commonly employed clinically to treat patients with claudication (3 compressions/min).

Physical activity maintains aortic endothelium-dependent relaxation in the obese type 2 diabetic OLETF rat.

We tested the hypothesis that physical activity can attenuate the temporal decline of ACh-induced endothelium-dependent relaxation during type 2 diabetes mellitus progression in the Otsuka Long-Evans Tokushima fatty (OLETF) rat. Sedentary OLETF rats exhibited decreased ACh-induced abdominal aortic endothelium-dependent relaxation from 13 to 20 wk of age (20-35%) and from 13 to 40 wk of age (35-50%). ACh-induced endothelium-dependent relaxation was maintained in the physically active OLETF group and control sedentary Long-Evans Tokushima Otsuka (LETO) group from 13 to 40 wk of age. Aortic pretreatment with N(G)-nitro-l-arginine (l-NNA), indomethacin (Indo), and l-NNA + Indo did not alter the temporal decline in ACh-induced endothelium-dependent relaxation. Temporal changes in the protein expression of SOD isoforms in the aortic endothelium or smooth muscle did not contribute to the temporal decline in ACh-induced endothelium-dependent relaxation in sedentary OLETF rats. A significant increase in the 40-wk-old sedentary LETO and physically active OLETF rat aortic phosphorylated endothelial nitric oxide (p-eNOS)-to-eNOS ratio was observed versus 13- and 20-wk-old rats in each group that was not seen in the 40- versus 13- and 20-wk-old sedentary OLETF rats. These results suggest that temporal changes in the antioxidant system, EDHF, and cycloxygenase metabolite production in sedentary OLETF rat aortas do not contribute to the temporal decline in sedentary OLETF rat aortic ACh-induced endothelium-dependent relaxation seen with type 2 diabetes mellitus progression. We also report that physical activity in conjunction with aging in the OLETF rat results in a temporal increase in the aortic endothelial p-eNOS-to-eNOS ratio that was not seen in sedentary OLETF rats. These results suggest that the sustained aortic ACh-induced endothelium-dependent relaxation in aged physically active OLETF rats may be the result of an increase in active aortic eNOS.

The Peru Approach against the COVID-19 Infodemic: Insights and Strategies.

The COVID-19 epidemic has spawned an "infodemic," with excessive and unfounded information that hinders an appropriate public health response. This perspective describes a selection of COVID-19 fake news that originated in Peru and the government's response to this information. Unlike other countries, Peru was relatively successful in controlling the infodemic possibly because of the implementation of prison sentences for persons who created and shared fake news. We believe that similar actions by other countries in collaboration with social media companies may offer a solution to the infodemic problem.

Brachial artery retrograde flow increases with age: relationship to physical function.

The purpose of this study was to examine the flow velocity pattern of the brachial artery and to determine its relationship to measures of physical function. Subjects from the Louisiana Healthy Aging Study (n = 95; age = 84 +/- 10 years) were evaluated. Brachial artery flow velocities and dimensions were measured using high-resolution ultrasonography. The continuous scale of physical function and performance test (CS-PFP10) was used to assess physical function. This test is based on the performance of 11 activities of daily living. Total CS-PFP10 score was 39.51 +/- 21.21 U. Mean antegrade and retrograde velocities at rest were 14.2 +/- 4.7 and 3.6 +/- 2.2 cm/s, respectively. Ante-/retrograde ratio was 5.5 +/- 4.6. Brachial artery diameter was 4.3 +/- 0.7 mm. Pulse pressure and vascular conductance were 66 +/- 18 mmHg, and 0.9 +/- 0.5 ml/min/mmHg, respectively. Vascular conductance (r = -0.34), ante-/retrograde ratio (r = -0.42) and CS-PFP10 (r = -0.65) were inversely and retrograde velocity (r = 0.40) and pulse pressure (r = 0.36), were directly associated with age. Retrograde velocity was inversely related to vascular conductance (r = -0.27) and CS-PFP10 total score (r = -0.45). A MANOVA revealed that those with the higher CS-PFP10 scores had a lower retrograde velocity (P = 0.0001), but this association was, in part, age-dependent. Among nonagenarians (n = 52), those in the lower tertiles of the CS-PFP10 scores had significantly higher retrograde velocities compared to those in the higher tertiles (P = 0.035). These data indicate an increase in brachial retrograde velocity with age. These hemodynamic changes are related to a decline in physical function.

The association between flow-mediated dilation and physical function in older men.

UNLABELLED: The probability that an individual is able to live independently decreases sharply below the threshold score of 57 units on the physical functional performance (PFP-10) test. PURPOSE: To examine the relation between brachial artery flow-mediated dilation (BAFMD) on individual and total scores on the PFP-10. We hypothesized that lower scores on the PFP-10 test would be associated with lower BAFMD. METHODS: Sixty-four men (age, 84 +/- 11 yr) from the Louisiana Healthy Aging Study were studied. Participants were classified by their performance on the PFP-10 test (Class I, score <26; Class II, score between 26 and 57; and Class III, score > 57). BAFMD was assessed after 5 min of forearm occlusion, using high-resolution ultrasonography. RESULTS: The average total score on the PFP-10 test and BAFMD were 42.9 +/- 22 U and 2.76 +/- 2.13%, respectively. The BAFMD was associated with total PFP-10 score (r = 0.45, P = 0.0001) and age (r = -0.36, P = 0.003). BAFMD was significantly different (P = 0.001) between the PFP-10 classes (Class I, 1.44% [95% CI, 0.49-2.39]; Class II, 2.67% [95% CI, 1.95-3.38]; and Class III, 4.01% [95% CI, 3.16-4.85]). CONCLUSIONS: This study reports significant relationships between BAFMD and individual and combined measures of physical function in elderly men. More specifically, when individuals were categorized based on their PFP-10 total score, those in the highest functional class, exhibited the highest BAFMD, compared to those in the middle class, who had greater vasoreactivity than those in the lowest functional class.

Impact of Tai Chi on Peripheral Neuropathy Revisited: A Mixed-Methods Study.

Exercise may be beneficial to older persons living with peripheral neuropathy (PN), but maintaining an exercise program is challenging. After participating in a 12-week tai chi (TC) study, 12 participants requested classes continue. A mixed-methods design was used to explore long-term engagement of older persons with bilateral PN enrolled in a TC class for 18 months beyond the original 3-month study. Pre- and posttest measures of functional status and quality of life (QOL) were conducted. Focus groups were held after 18 months of twice-weekly classes. Psychosocial support was critical to participants' long-term commitment to exercise. Participants reported, and objective assessments confirmed, increased strength, balance, and stamina beyond that experienced in the original 12-week study. Changes in QOL scores were nonsignificant; however, qualitative data supported clinical significance across QOL domains. Results from this study support psychosocial and physical benefits of TC to older persons.

Influence of venous emptying on the reactive hyperemic blood flow response.

BACKGROUND: Previous research indicates that venous emptying serves as a stimulus for vasodilation in the human forearm. This suggests the importance of recognizing the potential influence of venous volume on reactive hyperemic blood flow (RHBF) following occlusion. The purpose of this study was to examine the influence of venous emptying on forearm vascular function. METHODS: Forearm RHBF, venous capacitance and venous outflow were examined in 35 individuals (age = 22 +/- 2 years), using mercury in-Silastic strain gauge plethysmography, at rest and following five minutes of upper arm occlusion using standard procedures (CONTROL). In addition, the same measures were obtained following five minutes of upper arm occlusion preceded by two minutes of passive arm elevation (Pre-elevation). RESULTS: Average resting arterial inflow was 2.42 +/- 1.11 ml x 100 ml(-1) x min(-1). RHBF and venous capacitance were significantly greater during Pre-elevation compared to CONTROL (RHBF; Pre-elevation: 23.76 +/- 5.95 ml x 100 ml(-1) x min(-1) vs. CONTROL: 19.33 +/- 4.50; p = 0.001), (venous capacitance; Pre-elevation: 2.74 +/- 0.89 % vs. CONTROL: 2.19 +/- 0.97, p = 0.001). Venous outflow did not differ between the two conditions. CONCLUSION: Venous emptying prior to upper arm occlusion results in a significant greater RHBF response and venous capacitance. Recognition of the influence of venous volume on RHBF is particularly important in studies focusing on arterial inflow, and also provides further evidence for the interplay between the venous and arterial system.

Effect of electron radiation on vasomotor function of the left anterior descending coronary artery.

The left anterior descending (LAD, interventricular) coronary artery provides the blood supply to the mid-region of the heart and is a major site of vessel stenosis. Changes in LAD function can have major effects on heart function. In this report, we examined the effect of electron simulated solar particle event (eSPE) radiation on LAD function in a porcine animal model. Vasodilatory responses to adenosine diphosphate (ADP; 10(−9)­10(−4) M), bradykinin (BK; 10(−11)­10(−6) M), and sodium nitroprusside (SNP; 10(−10)­10(−4) M) were assessed. The LAD arteries from Control (non-irradiated) and the eSPE (irradiated) animals were isolated and exhibited a similar relaxation response following treatment with either ADP or SNP. In contrast, a significantly reduced relaxation response to BK treatment was observed in the eSPE irradiated group, compared to the control group. These data demonstrate that simulated SPE radiation exposure alters LAD function.

Epicardial adipose excision slows the progression of porcine coronary atherosclerosis.

BACKGROUND: In humans there is a positive association between epicardial adipose tissue (EAT) volume and coronary atherosclerosis (CAD) burden. We tested the hypothesis that EAT contributes locally to CAD in a pig model. METHODS: Ossabaw miniature swine (n=9) were fed an atherogenic diet for 6 months to produce CAD. A 15 mm length by 3-5 mm width coronary EAT (cEAT) resection was performed over the middle segment of the left anterior descending artery (LAD) 15 mm distal to the left main bifurcation. Pigs recovered for 3 months on atherogenic diet. Intravascular ultrasound (IVUS) was performed in the LAD to quantify atheroma immediately after adipectomy and was repeated after recovery before sacrifice. Coronary wall biopsies were stained immunohistochemically for atherosclerosis markers and cytokines and cEAT was assayed for atherosclerosis-related genes by RT-PCR. Total EAT volume was measured by non-contrast CT before each IVUS. RESULTS: Circumferential plaque length increased (p<0.05) in the proximal and distal LAD segments from baseline until sacrifice whereas plaque length in the middle LAD segment underneath the adipectomy site did not increase. T-cadherin, scavenger receptor A and adiponectin were reduced in the intramural middle LAD. Relative to control pigs without CAD, 11ß-hydroxysteroid dehydrogenase (11ßHSD-1), CCL19, CCL21, prostaglandin D2 synthase, gp91phox [NADPH oxidase], VEGF, VEGFGR1, and angiotensinogen mRNAs were up-regulated in cEAT. EAT volume increased over 3 months. CONCLUSION: In pigs used as their own controls, resection of cEAT decreased the progression of CAD, suggesting that cEAT may exacerbate coronary atherosclerosis.

Intermittent pneumatic leg compressions enhance muscle performance and blood flow in a model of peripheral arterial insufficiency.

Despite the escalating prevalence in the aging population, few therapeutic options exist to treat patients with peripheral arterial disease. Application of intermittent pneumatic leg compressions (IPC) is regarded as a promising noninvasive approach to treat this condition, but the clinical efficacy, as well the mechanistic basis of action of this therapy, remain poorly defined. We tested the hypothesis that 2 wk of daily application of IPC enhances exercise tolerance by improving blood flow and promoting angiogenesis in skeletal muscle in a model of peripheral arterial insufficiency. Male Sprague-Dawley rats were subjected to bilateral ligation of the femoral artery and randomly allocated to treatment or sham groups. Animals were anesthetized daily and exposed to 1-h sessions of bilateral IPC or sham treatment for 14-16 consecutive days. A third group of nonligated rats was also studied. Marked increases in treadmill exercise tolerance (∼33%, P < 0.05) and improved muscle performance in situ (∼10%, P < 0.05) were observed in IPC-treated animals. Compared with sham-treated controls, blood flow measured with isotope-labeled microspheres during in situ contractions tended to be higher in IPC-treated animals in muscles composed of predominantly fast-twitch white fibers, such as the plantaris (∼93%, P = 0.02). Capillary contacts per fiber and citrate synthase activity were not significantly altered by IPC treatment. Collectively, these data indicate that IPC improves exercise tolerance in a model of peripheral arterial insufficiency in part by enhancing blood flow to collateral-dependent tissues.

Exercise does not attenuate early CAD progression in a pig model.

PURPOSE: This study was designed to examine the effects of high-fat (HF) diet and subsequent exercise training (Ex) on coronary arteries of an animal model of early stage CAD. We hypothesized that HF diet would induce early stage disease and promote a proatherogenic coronary phenotype, whereas Ex would blunt disease progression and induce a healthier anti-inflammatory environment reflected by the increased expression of antioxidant capacity and the decreased expression of inflammatory markers in both the macrovasculature and the microvasculature of the coronary circulation. METHODS: Immunohistochemistry in left anterior descending and right coronary arteries and immunoblots in left anterior descending and left ventricular arterioles were used to characterize the effects of HF diet and Ex on the progression of coronary atherosclerosis. RESULTS: Our results revealed that HF diet promoted a proatherogenic coronary endothelial cell phenotype as evidenced by the endothelial expression of inflammatory and oxidative stress markers. Ex did not significantly alter any of these immunohistochemical markers in conduit arteries; however, Ex did increase antioxidant protein content in left ventricular arterioles. CONCLUSIONS: We conclude that, at this early stage of CAD, Ex did not seem to modify vascular cell phenotypes of conduit coronary arteries from proatherogenic to a more favorable antiatherogenic status; however, Ex increased antioxidant protein content in coronary arterioles. These findings also support the idea that endothelial phenotype expression follows different patterns in the macrovasculature and microvasculature of the coronary circulation.

Effects of endurance exercise training, metformin, and their combination on adipose tissue leptin and IL-10 secretion in OLETF rats.

Adipose tissue inflammation plays a role in cardiovascular (CV) and metabolic diseases associated with obesity, insulin resistance, and type 2 diabetes mellitus (T2DM). The interactive effects of exercise training and metformin, two first-line T2DM treatments, on adipose tissue inflammation are not known. Using the hyperphagic, obese, insulin-resistant Otsuka Long-Evans Tokushima Fatty (OLETF) rat model, we tested the hypothesis that treadmill training, metformin, or a combination of these reduces the secretion of proinflammatory cytokines from adipose tissue. Compared with Long-Evans Tokushima Otsuka (LETO) control rats (L-Sed), sedentary OLETF (O-Sed) animals secreted significantly greater amounts of leptin from retroperitoneal adipose tissue. Conversely, secretion of interleukin (IL)-10 by O-Sed adipose tissue was lower than that in L-Sed animals. Examination of leptin and IL-10 secretion from adipose tissue in OLETF groups treated with endurance exercise training (O-EndEx), metformin treatment (O-Met), and a combination of these (O-E+M) from 20 to 32 wk of age indicated that 1) leptin secretion from adipose tissue was reduced in O-Met and O-E+M, but not O-EndEx animals; 2) adipose tissue IL-10 secretion was increased in O-EndEx and O-E+M but not in O-Met animals; and 3) only the combined treatment (O-E+M) displayed both a reduction in leptin secretion and an increase in IL-10 secretion. Leptin and IL-10 concentrations in adipose tissue-conditioned buffers were correlated with their plasma concentrations, adipocyte diameters, and total adiposity. Overall, this study indicates that exercise training and metformin have additive influences on adipose tissue secretion and plasma concentrations of leptin and IL-10.

Peripheral circulation.

Blood flow (BF) increases with increasing exercise intensity in skeletal, respiratory, and cardiac muscle. In humans during maximal exercise intensities, 85% to 90% of total cardiac output is distributed to skeletal and cardiac muscle. During exercise BF increases modestly and heterogeneously to brain and decreases in gastrointestinal, reproductive, and renal tissues and shows little to no change in skin. If the duration of exercise is sufficient to increase body/core temperature, skin BF is also increased in humans. Because blood pressure changes little during exercise, changes in distribution of BF with incremental exercise result from changes in vascular conductance. These changes in distribution of BF throughout the body contribute to decreases in mixed venous oxygen content, serve to supply adequate oxygen to the active skeletal muscles, and support metabolism of other tissues while maintaining homeostasis. This review discusses the response of the peripheral circulation of humans to acute and chronic dynamic exercise and mechanisms responsible for these responses. This is accomplished in the context of leading the reader on a tour through the peripheral circulation during dynamic exercise. During this tour, we consider what is known about how each vascular bed controls BF during exercise and how these control mechanisms are modified by chronic physical activity/exercise training. The tour ends by comparing responses of the systemic circulation to those of the pulmonary circulation relative to the effects of exercise on the regional distribution of BF and mechanisms responsible for control of resistance/conductance in the systemic and pulmonary circulations.

Daily physical activity enhances reactivity to insulin in skeletal muscle arterioles of hyperphagic Otsuka Long-Evans Tokushima Fatty rats.

Insulin-mediated glucose disposal is dependent on the vasodilator effects of insulin. In type 2 diabetes, insulin-stimulated vasodilation is impaired as a result of an imbalance in NO and ET-1 production. We tested the hypothesis that chronic voluntary wheel running (RUN) prevents impairments in insulin-stimulated vasodilation associated with obesity and type 2 diabetes independent of the effects of RUN on adiposity by randomizing Otsuka Long Evans Tokushima Fatty (OLETF) rats, a model of hyperphagia-induced obesity and type 2 diabetes, to 1) RUN, 2) caloric restriction (CR; diet adjusted to match body weights of RUN group), or 3) sedentary control (SED) groups (n = 8/group) at 4 wk. At 40 wk, NO- and ET-1-mediated vasoreactivity to insulin (1-1,000 µIU/ml) was assessed in the presence of a nonselective ET-1 receptor blocker (tezosentan) or a NO synthase (NOS) inhibitor [N(G)-nitro-L-arginine methyl ester (L-NAME)], respectively, in second-order arterioles isolated from the white portion of the gastrocnemius muscle. Body weight, fasting plasma glucose, and hemoglobin A1c were lower in RUN and CR than SED (P < 0.05); however, the glucose area under the curve (AUC) following the intraperitoneal glucose tolerance test was lower only in the RUN group (P < 0.05). Vasodilator responses to all doses of insulin were greater in RUN than SED or CR in the presence of a tezosentan (P < 0.05), but group differences in vasoreactivity to insulin with coadministration of L-NAME were not observed. We conclude daily wheel running prevents obesity and type 2 diabetes-associated declines in insulin-stimulated vasodilation in skeletal muscle arterioles through mechanisms that appear to be NO mediated and independent of attenuating excess adiposity in hyperphagic rats.

Epicardial fat gene expression after aerobic exercise training in pigs with coronary atherosclerosis: relationship to visceral and subcutaneous fat.

Epicardial adipose tissue (EAT) is contiguous with coronary arteries and myocardium and potentially may play a role in coronary atherosclerosis (CAD). Exercise is known to improve cardiovascular disease risk factors. The purpose of this study was to investigate the effect of aerobic exercise training on the expression of 18 genes, measured by RT-PCR and selected for their role in chronic inflammation, oxidative stress, and adipocyte metabolism, in peri-coronary epicardial (cEAT), peri-myocardial epicardial (mEAT), visceral abdominal (VAT), and subcutaneous (SAT) adipose tissues from a castrate male pig model of familial hypercholesterolemia with CAD. We tested the hypothesis that aerobic exercise training for 16 wk would reduce the inflammatory profile of mRNAs in both components of EAT and VAT but would have little effect on SAT. Exercise increased mEAT and total heart weights. EAT and heart weights were directly correlated. Compared with sedentary pigs matched for body weight to exercised animals, aerobic exercise training reduced the inflammatory response in mEAT but not cEAT, had no effect on inflammatory genes but preferentially decreased expression of adiponectin and other adipocyte-specific genes in VAT, and had no effect in SAT except that IL-6 mRNA went down and VEGFa mRNA went up. We conclude that 1) EAT is not homogeneous in its inflammatory response to aerobic exercise training, 2) cEAT around CAD remains proinflammatory after chronic exercise, 3) cEAT and VAT share similar inflammatory expression profiles but different metabolic mRNA responses to exercise, and 4) gene expression in SAT cannot be extrapolated to VAT and heart adipose tissues in exercise intervention studies.