Background: Brachial artery endothelium-dependent dilation (flow-mediated dilation, FMD) is impaired with aging and is associated with increased risk for cardiovascular disease (CVD). Interventions that improve brachial artery FMD may help prevent age-related CVD. The purpose of this study was to determine if regular aerobic exercise increases brachial artery FMD in healthy middle-aged/older (ma/o) men and postmenopausal women. Methods: In a randomized controlled prospective study, non-obese (body mass index <30 kg/m2) ma/o previously sedentary adults (n=36, age 55–79 years) without CVD were studied before and after 8-weeks of vigorous daily walking (n=26, age 63±1 yrs) or non-exercise control (n=10, age 60±1 yrs). In a cross-sectional analysis, healthy ma/o sedentary (n=102, age 62±1 yrs) and endurance exercise-trained (n=65, age 62±1 yrs) men and postmenopausal women were studied. Results: Daily vigorous walking (~6 days/week, ~50 min/day, ~70% maximal heart rate) increased treadmill exercise time by ~2...
Middle‐aged and older (MA/O) adults who perform habitual aerobic exercise demonstrate enhanced vascular endothelial function compared with their sedentary peers, but the molecular mechanisms involved are unknown. Brachial artery flow‐mediated dilation, a measure of endothelium‐dependent dilation, was 34% higher (6.8 ± 0.9 vs. 5.1 ± 0.4 %δ, P<0.05) in regularly exercising (EX, n=12, 62 ± 2 yrs, 8M/4F) vs. sedentary (SED; n=25, age 62 ± 1 yrs, 12M/13F) healthy MA/O adults, whereas endothelium‐independent dilation to sublingual nitroglycerin was not different (29.3 ± 1.8 vs. 26.7 ± 1.4 %δ, P=0.29). In endothelial cells obtained from the brachial artery, expression of nitrotyrosine (NT), a cellular marker of oxidative stress (0.48 ± 0.07 vs. 0.74 ± 0.10 immunofluorescent intensity/HUVEC intensity), NADPH oxidase p47 phox , a subunit of the oxidant enzyme NADPH oxidase (0.41 ± 0.04 vs. 0.76 ± 0.09), and nuclear factor κB (NFκB), a redox‐sensitive proinflammatory transcription factor (0.39 ± 0.04 vs. 0.64 ± 0.06), were 35‐50% lower in EX, whereas manganese superoxide dismutase (MnSOD), a mitochondrial antioxidant enzyme, was 74% higher (0.48 ± 0.07 vs. 0.28 ± 0.04) (all P<0.05 vs. SED). NT was positively related to NADPH oxidase p47 phox (r=0.64, P<0.01) and NFκB (r=0.29, P=0.05), but not to MnSOD. Compared with their sedentary peers, habitually exercising MA/O adults have reduced vascular endothelial cell oxidative stress related to decreased NADPH oxidase and NFκB. Supported by NIH AG000279, AG013038, AG022241, AG006537, and RR00051.
Depression and preeclampsia share risk factors and are bi-directionally associated with increased risk for each other. Despite epidemiological evidence linking selective serotonin reuptake inhibitors (SSRIs) in pregnancy to preeclampsia, serotonin (5-HT) and vasopressin (AVP) secretion mechanisms suggest that SSRIs may attenuate preeclampsia risk. However, there is a need to clarify the relationship between SSRIs and preeclampsia in humans to determine therapeutic potential. This retrospective cohort study included clinical data from 9558 SSRI-untreated and 9046 SSRI-treated pregnancies. In a subcohort of 233 pregnancies, early pregnancy (< 20 weeks) maternal plasma copeptin, an inert and stable AVP prosegment secreted 1:1 with AVP, was measured by enzyme-linked immunosorbent assay. Diagnoses and depression symptoms (Patient Health Questionnaire-9 [PHQ-9]) were identified via medical records review. Descriptive, univariate, and multivariate regression analyses were conducted (α = 0.05). SSRI use was associated with decreased preeclampsia after controlling for clinical confounders (depression severity, chronic hypertension, diabetes, body mass index, age) (OR = 0.9 [0.7-1.0], p = 0.05). Moderate-to-severe depression symptoms were associated with significantly higher copeptin secretion than mild-to-no depression symptoms (240 ± 29 vs. 142 ± 10 ng/mL, p < 0.001). SSRIs significantly attenuated first trimester plasma copeptin (78 ± 22 users vs. 240 ± 29 ng/ml non-users, p < 0.001). In preeclampsia, SSRI treatment was associated with significantly lower copeptin levels (657 ± 164 vs. 175 ± 134 ng/mL, p = 0.04). Interaction between SSRI treatment and preeclampsia was also significant (p = 0.04). SSRIs may modulate preeclampsia risk and mechanisms, although further studies are needed to investigate the relationships between 5-HT and AVP in depression and preeclampsia.
Abstract Declining episodic memory is common among otherwise healthy older adults, in part due to negative effects of aging on hippocampal circuits. However, there is significant variability between individuals in severity of aging effects on the hippocampus and subsequent memory decline. Importantly, variability may be influenced by modifiable protective physiological factors such as cardiorespiratory fitness (CRF). More research is needed to better understand which aspects of cognition that decline with aging benefit most from CRF. The current study evaluated the relation of CRF with learning rate on the episodic associative learning (EAL) task, a task designed specifically to target hippocampal‐dependent relational binding and to evaluate learning with repeated occurrences. Results show higher CRF was associated with faster learning rate. Larger hippocampal volume was also associated with faster learning rate, though hippocampal volume did not mediate the relationship between CRF and learning rate. Furthermore, to support the distinction between learning item relations and learning higher‐order sequences, which declines with aging but is largely reliant on extra‐hippocampal learning systems, we found learning rate on the EAL task was not related to motor sequence learning on the alternating serial reaction time task. Motor sequence learning was also not correlated with hippocampal volume. Thus, for the first time, we show that both higher CRF and larger hippocampal volume in healthy older adults are related to enhanced rate of relational memory acquisition.
The early mechanisms and genetic risk factors driving the pathogenesis of preeclampsia (PE), a cardiovascular disorder of pregnancy, remain largely unclear. Various hormone activators of Gα q second-messenger signaling pathways have been implicated in PE. Regulator of G-protein Signaling 2 (RGS2) acts as an endogenous terminator of Gα q signaling and previous studies identified a SNP (rs4606), which results in reduced RGS2 mRNA, as a risk factor for development of PE and its sequelae. We hypothesized reduced placental expression of RGS2 may precipitate the development of PE due to disinhibited Gα q signaling. In silico reanalysis of publically available dataset GSE75010 revealed RGS2 mRNA is reduced in placentas from pre-term PE pregnancies compared to normal pre-term pregnancies (con: 8.73 ± 0.07 n=35, PE: 8.37 ± 0.055 n=49, p<0.05). Using human placental tissue samples from the University of Iowa Maternal-Fetal Tissue Bank, we confirmed RGS2 mRNA is reduced in PE placentas (19% of control, p<0.05), despite a lack of correlation between the rs4606 SNP and PE. Additionally, in further reanalysis of other datasets, RGS2 mRNA is among the highest-expressed RGS member in normal human placenta, and appears to be selectively reduced in syncytio- and invasive cytotrophoblasts during PE (GSE93839, -26.3%, -23.3% of control). We next examined RGS2 expression in mouse placenta by FISH and found RGS2 mRNA colocalizes with markers of syncytiotrophoblast II (GCMA) and spongiotrophoblast (Tpbpα) layers. To test the effect of RGS2 loss during pregnancy, wildtype C57BL/6J female mice were mated with RGS2-deficient sires and developed diastolic hypertension, placental hypoxia by HIF1α ELISA (con 0.144±0.004, RGS2-KO 0.155±0.004 AU, p<0.05, n=5 each), and reduced placental PlGF mRNA (fold; con=1.0 n=7, RGS2-KO=0.23 n=12, p<0.05), compared to females mated with RGS2 littermate sires. These data support the concept that loss of RGS2 may contribute to the pathogenesis of PE rather than simply correlating with the disorder. Taken together, we have shown placental RGS2 is suppressed in PE, RGS2 is present in cytoplasm of specific layers of trophoblasts, and loss of feto-placental RGS2 is sufficient to cause placental hypoxia and maternal diastolic hypertension.
Objective: Central artery reservoir pressure and excess pressure (XSP) are associated with cardiovascular disease (CVD) events and mortality. However, sex differences in the trajectory of central reservoir pressure and XSP with advancing age and their relations with vascular markers of subclinical CVD risk are incompletely understood. Therefore, we tested the hypothesis that central reservoir pressure and XSP would be positively associated with advancing age and vascular markers of subclinical CVD risk in men and women. Method: Healthy adults ( n = 398; aged 18–80 years, 60% female individuals) had central (carotid) artery pressure waveforms acquired by applanation tonometry. Reservoir pressure and XSP peaks and integrals were derived retrospectively from carotid pressure waveforms using custom written software. Carotid artery intimal–medial thickness (IMT) was measured by ultrasonography, and aortic stiffness was determined from carotid–femoral pulse wave velocity (cfPWV). Results: Reservoir pressure peak, reservoir pressure integral and XSP integral were higher with age in both men and women ( P < 0.05), whereas XSP peak was lower with age in men ( P < 0.05). In women, both reservoir pressure peak ( β = 0.231, P < 0.01) and reservoir pressure integral ( β = 0.254, P < 0.01) were associated with carotid artery IMT, and reservoir pressure peak was associated with cfPWV ( β = 0.120, P = 0.02) after adjusting for CVD risk factors. Conclusion: Central artery reservoir pressure and XSP were higher with advancing age in men and women, and reservoir pressure peak was associated with both carotid artery wall thickness and aortic stiffness in women but not men. Central reservoir pressure peak may provide some insight into sex differences in vascular remodeling and subclinical CVD risk with advancing age in healthy adults.
Recent evidence suggests that elevated sympathetic nerve activity (SNA) may increase large central elastic artery stiffness (i.e., carotid, aorta), a robust independent predictor of cardiovascular disease. However, experimental manipulations involving increased (e.g., handgrip exercise) or decreased (e.g., ganglionic blockade) SNA in humans have also evoked concomitant changes in arterial blood pressure (BP) making interpretation difficult. Therefore, we tested the hypothesis that acute elevations in SNA increase central artery stiffness independent of BP. First, in 7 young healthy men (20 ± 1 yrs; 26 ± 1 kg/m 2 ), carotid artery compliance was assessed at baseline and during a moderate level of lower body negative pressure (LBNP, −45mmHg), a stimulus known to significantly increase SNA without major changes in BP. Next, carotid‐femoral pulse wave velocity (PWV), the gold standard assessment of aortic stiffness, and resting muscle SNA (MSNA) were assessed in a larger sample of healthy individuals (n=30; 37 ± 3 yrs; 11 women) and correlated. During LBNP, baroreflex‐mediated increases in heart rate were observed (BL: 59 ± 3 vs. LBNP: 80 ± 5 bpm, P<0.05), but mean BP was unchanged (BL: 79 ± 1 vs. LBNP: 81 ± 1 mmHg, P>0.05). Carotid artery compliance was significantly reduced during LBNP compared with baseline (BL: 1.15 ± 0.11 vs. LBNP: 0.71 ± 0.1 mm 2 /mmHg×10 −2 , P<0.05) in addition to reductions in brachial artery compliance (BL: 0.1 ± 0.03 vs. LBNP: 0.07 ± 0.02 mm 2 /mmHg×10 −2 , P<0.05). In the larger sample, carotid artery compliance was moderately associated with resting MSNA (R=−0.374, P=0.055); however, there was a stronger association between carotid‐femoral PWV and resting MSNA (R=0.583, P<0.01) that persisted after adjusting for BP and sex (R=0.471, P<0.01). Together, these preliminary data suggest that SNA acutely increases large central elastic artery stiffness in humans independent of changes in BP, and that tonically elevated resting SNA may contribute to higher large central elastic artery stiffness. Support or Funding Information NIH T32 HL007121, P01HL014388, U54TR001356 and American Heart Association 13SDG143400012
We read with interest the study by Goldfine et al. (1) in the recent issue of Diabetes Care that reported that 3 and 6 months of oral salsalate treatment, as part of the multicenter Targeting Inflammation Using Salsalate in Type 2 Diabetes (TINSAL-T2D) trial, had no effect on brachial artery flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (measurements of endothelium-dependent and -independent dilation, respectively) in patients with type 2 diabetes (T2D). The authors concluded that their findings suggest that 1 ) salsalate does not inhibit vascular inflammation, 2 ) inflammation does not cause endothelial dysfunction in patients with T2D, or 3 ) the potential benefits of salsalate were masked by the unfavorable changes in serum …
Healthy middle‐aged/older (MA/O) sedentary men demonstrate vascular endothelial dysfunction with increased endothelial expression of nuclear factor‐kappa B (NFκB), a key proinflammatory nuclear transcription factor. However, there is no direct evidence that NFκB‐associated vascular inflammation mediates endothelial dysfunction in MA/O adults. High doses of Salsalate (4500 mg/d; therapeutic [plasma] 22.2 ± 1.7 mg/100ml, mean ± SE), an aspirin‐like agent that inhibits NFκB, was ingested for 4 days (randomized, placebo‐controlled, double‐blind crossover design) by 10 non‐diabetic overweight or obese MA/O men (62 ± 2 y; BMI 31.4 ± 2 kg/m 2 ) with low‐grade inflammation (plasma C‐reactive protein 2.0 ± 0.7 mg/L). Salsalate reduced total (−30%: 0.42 ± 0.07 vs. 0.60 ± 0.09 intensity/HUVEC intensity, P=0.03) and nuclear (−23%: 128 ± 25 vs. 167 ± 24 total intensity, P=0.06) expression of NFκB p65 in vascular endothelial cells (quantitative immunofluorescence), and increased endothelium‐dependent dilation (EDD, brachial artery flow‐mediated dilation) by 100% (6.2 ± 0.6 vs. 3.1 ± 0.6%, P<0.001) without affecting endothelium‐independent dilation (brachial artery dilation to sublingual nitroglycerin) (19.5 ± 2.2 vs. 19.3 ± 1.6%, P=0.80). These results support the idea that NFκB‐associated vascular inflammation mediates endothelial dysfunction in MA/O overweight/obese men. NIH AG006537, AG013038, AG022241
