Arturo A. Arce-Esquivel

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.

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.

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.

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.

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.

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

•  What is the central question of this study? While it is well accepted that long‐term physical inactivity is associated with an increased cardiovascular risk, the early effects of adoption of a sedentary lifestyle on the vasculature have not been characterized at the molecular level. •  What is the main finding and its importance? The primary finding of this study is that transition from high to low physical activity produces modest changes in mRNA expression for some pro‐and anti‐atherogenic genes, but that both the genes affected and direction of change differ between iliac and renal artery. This heterogeneous effect of short‐term physical inactivity could be attributed to the distinct alterations in haemodynamic forces between these arteries.

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.

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.

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 Training Improves Vasoreactivity in the Knee Artery

Physical activity has been shown to enhance endothelial function of central and peripheral vascular beds. The primary purpose of the present study was to test the hypothesis that a short-term exercise training program would result in enhanced endothelium-dependent vasorelaxation of a major artery supplying blood flow to the knee joint, the middle genicular artery. Female Yucatan miniature swine were randomly assigned into exercise trained (n=7) or sedentary (n=7) groups. Exercise trained pigs underwent a daily exercise training program on treadmills for 7 days. In vitro assessment of vasorelaxation was determined in a dose response manner by administrating increasing doses of 3 different dilators; adenosine diphosphate, bradykinin, and sodium nitroprusside. The role of nitric oxide synthase and cyclooxygenase pathways in vasomotor responses was evaluated with specific inhibitors using nitro-L-arginine methyl ester and indomethacin incubation, respectively. The results of this investigation indicate that adenosine and bradykinin-induced endothelium-dependent vasorelaxation were significantly enhanced in middle genicular artery from exercise trained pigs (p<0.05). Endothelium-independent vasorelaxation was not altered with exercise training as determined by the response to sodium nitroprusside. The findings of the present investigation indicate that short-term exercise training enhances endothelial function of middle genicular artery through adaptations in the nitric oxide synthase and by non-nitric oxide synthase, non-cyclooxygenase pathways.