Physical Activity, Inactivity and Sedentary Behavior: Mediators of Vascular Health

As part of the mini-symposium entitled Divergent Impacts of Physical Activity and Sedentary Behavior on Glucose Intolerance and Vascular Function: From Laboratory to Clinic, this presentation shares data on the role of increased physical activity and sedentary behavior in mediating cardiovascular disease

Effect of long-term exercise on endothelial progenitor cells in healthy humans

Endothelial progenitor cells (EPCs) are derived from the bone marrow and have been found to play a role in postnatal neovascularization and re-endothelialization. Reduced EPC number and function have been associated with death from cardiovascular diseases, CVD risk factors, and endothelial dysfunction. Oxidative stress, specifically, oxidized LDL (OxLDL) has been shown to decrease EPC number and function, and increase EPC senescence in vitro. Regular physical activity is related to lower rates of CVD; however the mechanisms underlying the benefits of exercise in the prevention of CVD are not fully clear. Exercise may improve the number, and function of EPCs while improving oxidative stress status. The primary purpose of this study was to compare CD34+/KDR+ EPC number, EPC clonogenic capacity, and senescence, in healthy men that have participated in greater than 20 years of moderate- to high-intensity exercise with low-active control subjects. To assess the effect of physical inactivity on these markers, a subset of exercisers (n=10) stopped exercising for 10 days after which, measures of EPC number, colony forming units, and senescence, endothelial function and oxidative stress were re-evaluated. Results showed that, CD34+/KDR+ cell number, CFU-Hill colonies, and EPC senescence were not statistically different between athlete and control groups. CD34+/KDR+ cell number was closely related to endothelial function. Specifically, the forearm blood flow response to reactive hyperemia was correlated with CD34+/KDR+ number in sedentary participants. Additionally, 5 athletes significantly decreased their CD34+/KDR+ number, which was related to a significant decline in endothelial function, indicating that regular physical activity is important for some athletes to maintain healthy endothelial function, perhaps through the maintenance of elevated number of circulating CD34+/KDR+ cells. CFU-Hill colony number was strongly correlated with hyperemic blood flow response in control participants and related to oxLDL independent of physical activity status. Athletes who participated in 10-days of exercise detraining demonstrated a significant decrease in EPC senescence, which was related to improved total antioxidant capacity. Overall, these results show that CD34+/KDR+ number is closely related to endothelial function. Moreover, the function of EPCs appears to be affected by oxidative stress and antioxidant availability

Ovariectomy Induces Early Changes in Cardiac Fibrosis and Angiotensin II Gene Expression

Postmenopausal women have an increased risk for heart disease. Ovariectomized mouse models show changes in body weight, adipose tissue, and systemic inflammation within 8-12 weeks following ovariectomy. These pathological changes may contribute to cardiac dysfunction after menopause. However, early changes in cardiac markers that may lead to dysfunction and disease remain unclear. Objective: To evaluate differences in cardiac gene expression between 8-week post-ovariectomy and control mice. Methods: Myocardial RNA was isolated from ovariectomized (OVX, n=10) and sham surgery (SHAM, n=10) adult mice 8 weeks following surgery. Fetal gene program, fibrosis, and angiotensin II gene expression were determined via RT-PCR. Differences between groups were analyzed using two sample t-tests. Results: Compared to SHAM, OVX mice exhibited a fetal gene expression pattern similar to that observed in failing hearts including increased B-type natriuretic peptide (p=0.02), atrial natriuretic peptide (p=0.06) and alpha skeletal actin (p=0.01) and decreased alpha and beta myosin heavy chain isoform expression (p=0.05, p=0.02, respectively). Expression of fibrotic genes vimentin (p=0.01), fibronectin (p=0.02), collagen1 (p=0.04), and collagen3 (p=0.03) were greater in OVX compared with SHAM. Lastly, angiotensin II was also significantly greater in OVX (p=0.001). Conclusion: Ovariectomized mice begin to exhibit maladaptive gene expression within 8 weeks after surgery, indicating that ovarian hormone loss initiates a pathological response in the heart at early time points that may be related to angiotensin II-induced cardiac fibrosis

Pericyte NF-κB Activation Enhances Endothelial Cell Proliferation and Proangiogenic Cytokine Secretion

Pericytes are skeletal muscle resident, multipotent stem cells that are localized to capillaries. They respond to damage through activation of nuclear-factor kappa-B (NF-κB), a transcription factor that regulates many cellular processes including inflammation. Research has shown that pericyte NF-κB activation positively affects myoblast proliferation. It is unknown how pericyte NF-κB affects signaling and proliferation of endothelial cells, an important component of muscle tissue microcirculation. PURPOSE: To determine the effects of altered pericyte NF-κB activity on endothelial cell proliferation and identify inflammatory factors involved in this cell-cell signaling. METHODS: Human primary pericytes were transfected with vectors designed to increase or decrease NF-κB activity (or empty vector control). Transfected pericytes were co-cultured with human microvascular endothelial cells (HMVECs) using transwell inserts. HMVEC proliferation was assessed via cell counting at 24 and 48 hr. Secreted cytokines in cell culture supernatants were screened using a Luminex multiplex assay. RESULTS: HMVEC proliferation was greater in the increased pericyte NF-κB activity condition compared to the decreased NF-κB condition at 24 and 48 hr (1.3 fold, p=0.002). At 24 hr, cytokine secretion was greater in the increased NF-κB condition compared to control and decreased NF-κB conditions for 14 cytokines, including interleukin-8 (IL-8; 6.4 fold, p CONCLUSION: NF-κB activation in pericytes caused increased HMVEC proliferation, which may have been mediated by proinflammatory and proangiogenic cytokines known to be under the transcriptional regulation of NF-κB

High-Frequency Electrically Stimulated Skeletal Muscle Contractions Increase p70\u3csup\u3es6k\u3c/sup\u3e Phosphorylation Independent of Known IGF-I Sensitive Signaling Pathways

Insulin-like growth factor (IGF-I) is hypothesized to be a critical upstream regulator of mammalian target of rapamycin (mTOR)-regulated protein synthesis with muscle contraction. We utilized a mouse model that expresses a skeletal muscle specific dominant-negative IGF-I receptor to investigate the role of IGF-I signaling of protein synthesis in response to unilateral lengthening contractions (10 sets, 6 repetitions, 100. Hz) at 0 and 3. h following the stimulus. Our results indicate that one session of high frequency muscle contractions can activate mTOR signaling independent of signaling components directly downstream of the receptor

Effects of Gender and Hypovolemia on Sympathetic Neural Responses to Orthostatic Stress

We tested the hypothesis that women have blunted sympathetic neural responses to orthostatic stress compared with men, which may be elicited under hypovolemic conditions. Muscle sympathetic nerve activity (MSNA) and hemodynamics were measured in eight healthy young women and seven men in supine position and during 6 min of 60° head-up tilt (HUT) under normovolemic and hypovolemic conditions (randomly), with ∼4-wk interval. Acute hypovolemia was produced by diuretic (furosemide) administration ∼2 h before testing. Orthostatic tolerance was determined by progressive lower body negative pressure to presyncope. We found that furosemide produced an ∼13% reduction in plasma volume, causing a similar increase in supine MSNA in men and women (mean ± SD of 5 ± 7 vs. 6 ± 5 bursts/min; P = 0.895). MSNA increased during HUT and was greater in the hypovolemic than in the normovolemic condition (32 ± 6 bursts/min in normovolemia vs. 44 ± 15 bursts/min in hypovolemia in men, P = 0.055; 35 ± 9 vs. 45 ± 8 bursts/min in women, P \u3c 0.001); these responses were not different between the genders (gender effect: P = 0.832 and 0.814 in normovolemia and hypovolemia, respectively). Total peripheral resistance increased proportionately with increases in MSNA during HUT; these responses were similar between the genders. However, systolic blood pressure was lower, whereas diastolic blood pressure was similar in women compared with men during HUT, which was associated with a smaller stroke volume or stroke index. Orthostatic tolerance was lower in women, especially under hypovolemic conditions. These results indicate that men and women have comparable sympathetic neural responses during orthostatic stress under normovolemic and hypovolemic conditions. The lower orthostatic tolerance in women is predominantly because of a smaller stroke volume, presumably due to less cardiac filling during orthostasis, especially under hypovolemic conditions, which may overwhelm the vasomotor reserve available for vasoconstriction or precipitate neurally mediated sympathetic withdrawal and syncope

Physical Activity and Exercise for Hot Flashes: Trigger or Treatment?

Importance and Objective: Hot flashes (HFs) are a prevalent feature of menopause. Hot flashes can be bothersome and affect quality of life. However, HFs have also been associated with the risk for cardiovascular disease. Therefore, providing current evidence on the effect of therapies to reduce HFs can help patients and providers with decision making. This review provides details on the scientific evidence to date related to the effect of physical activity (PA) and exercise to alter the HF experience in women Methods: The PubMed database was searched between June 2020 and June 2022 for currently available evidence regarding the relation between PA and exercise and HFs. Our analysis included randomized control trials on exercise training, epidemiological studies, and studies evaluating acute exercise on the self-reported and objectively measured HF experience in addition to systematic reviews on the topic published as of June 2022. Discussion and Conclusions: The majority of evidence from randomized control trials indicates that aerobic and resistance exercise training lead to a decrease in subjectively experienced HFs. The limited available studies on acute exercise indicate that a bout of moderate-intensity exercise may decrease objectively measured and self-reported HFs but acute increases in PA intensity above accustomed levels may influence subjective HF experience. Some evidence suggests that for those with depression, habitual PA may be an effective way to reduce HF symptoms. Weighing the avail- able evidence, for people who experience HFs, engaging in regular moderate-intensity PA, including aerobic and resistance exercise, may be an effective therapy to reduce HFs and women should be counseled on the benefits of regular, moderate exercise. However, significant gaps in knowledge remain about the optimal exercise prescription, effectiveness for a diverse population, meaning of differences between objective and subjective experience, and mechanisms that lead to changes in HFs

Glucose and Acute Exercise Influence Factors Secreted by Circulating Angiogenic Cells In Vitro

Circulating angiogenic cells (CAC) influence vascular repair through the secretion of proangiogenic factors and cytokines. While CAC are deficient in patients with diabetes and exercise has a beneficial effect on CACs, the impact of these factors on paracrine secretion from CAC is unknown. We aimed to determine whether the in vitro secretion of selected cytokines and nitric oxide (NO) from CAC is influenced by hyperglycemia and acute exercise. Colony-forming unit CAC (CFU-CAC) were cultured from young active men (n = 9, 24 ± 2 years) at rest and after exercise under normal (5 mmol/L) and elevated (15 mmol/L) glucose. Preliminary relative multiplex cytokine analysis revealed that CAC conditioned culture media contained three of six measured cytokines: transforming growth factor-beta-1 (TGFβ1), tumor necrosis factor alpha (TNFα), and monocyte chemotactic protein-1 (MCP-1). Single quantitative cytokine analysis was used to determine the concentration of each cytokine from the four conditions. NO was measured via Griess assay. There was a significant effect of CAC exposure to in vivo exercise on in vitro TGFβ1 secretion (P = 0.024) that was independent of glucose concentration. There was no effect of glucose or acute exercise on TNFα or MCP-1 concentration (bothP \u3e 0.05). The concentration of NO from CFU-CAC cultured in elevated glucose was lower following acute exercise (P = 0.002) suggesting that exercise did not maintain NO secretion under hyperglycemic conditions. Our results identify paracrine signaling factors that may be responsible for the proangiogenic function of CFU-CAC and an influence of acute exercise and elevated glucose on CFU-CAC soluble factor secretion

Follicle-Stimulating Hormone is Associated with Lipids in Postmenopausal Women

Objective: The purpose of this study was to evaluate the relation between FSH and lipid levels in postmenopausal women from the Kuopio Ischaemic Heart Disease Risk Factor Study. Methods: Postmenopausal women (n = 588) aged 53 to 73 years and not using hormone therapy were included. The relation between FSH and total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TGs) was evaluated using linear regression, adjusting for estradiol, body mass, smoking, and other hormonal and lifestyle factors. The relation between FSH, dyslipidemia, and abnormal lipid levels were also evaluated. Results: FSH was positively and linearly associated with TC (P = 0.001) and LDL-C (P = 0.01) in all participants, with stronger relations seen in younger compared with older postmenopausal women. FSH was less strongly associated with HDL-C and TG. FSH was not associated with dyslipidemia; however, higher FSH was associated with increased risk of high TC (P = 0.02) and high LDL-C (P = 0.03). Conclusions: These data suggest that higher FSH in postmenopausal women is related to higher levels of both TC and LDL-C

Inhibition of Nitric Oxide Inhibition of Nitric Oxide Synthase Does Not Alter Dynamic Cerebral Autoregulation in Humans

The aim of this study was to determine whether inhibition of nitric oxide synthase (NOS) alters dynamic cerebral autoregulation in humans. Beat-to-beat blood pressure (BP) and cerebral blood flow (CBF) velocity (transcranial Doppler) were measured in eight healthy subjects in the supine position and during 60° head-up tilt (HUT). NOS was inhibited by intravenous N G-monomethyl-L-arginine (L-NMMA) infusion. Dynamic cerebral autoregulation was quantified by transfer function analysis of beat-to-beat changes in BP and CBF velocity. Pressor effects of L-NMMA on cerebral hemodynamics were compared with those of phenylephrine infusion. In the supine position, L-NMMA increased mean BP from 83 ± 3 to 94 ± 3 mmHg (P \u3c 0.01). However, CBF velocity remained unchanged. Consequently, cerebrovascular resistance index (CVRI) increased by 15% (P \u3c 0.05). BP and CBF velocity variability and transfer function gain at the low frequencies of 0.07-0.20 Hz did not change with L-NMMA infusion. Similar changes in mean BP, CBF velocity, and CVRI were observed after phenylephrine infusion, suggesting that increase in CVRI after L-NMMA was mediated myogenically by increase in arterial pressure rather than a direct effect of cerebrovascular NOS inhibition. During baseline tilt without L-NMMA, steady-state BP increased and CBF velocity decreased. BP and CBF velocity variability at low frequencies increased in parallel by 277% and 217%, respectively (P \u3c 0.05). However, transfer function gain remained unchanged. During tilt with L-NMMA, changes in steady-state hemodynamics and BP and CBF velocity variability as well as transfer gain and phase were similar to those without L-NMMA. These data suggest that inhibition of tonic production of NO does not appear to alter dynamic cerebral autoregulation in humans