Endothelial function typically exhibits a hormetic response to exercise. It is unknown whether endothelial damage occurs in response to acute exercise and could be a contributing mechanism. We sought to determine the effects of acute exercise on endothelial-derived circulating factors proposed to reflect endothelial integrity and activation. Young, healthy men ( n = 10) underwent 30-min moderate continuous (MOD) and high-intensity interval (HII) cycling exercise bouts. Venous blood samples were taken immediately before and after exercise for quantification of circulating endothelial cells (CECs), circulating angiogenic cells (CACs), apoptotic and activated endothelial microvesicles (EMVs), thrombomodulin (TM), von Willebrand factor (vWF), syndecan-1, and circulating microRNAs (ci-miRs) 126–3p and 126–5p. Endothelial function was assessed by flow-mediated dilation (FMD) of the brachial artery before, 10 min after, and 60 min after exercise. Numbers of CECs and EMVs were unchanged by either exercise bout ( P > 0.05). Numbers of all measured CAC subtypes decreased in response to MOD (21%–34%, P < 0.05), whereas only CD31+/34+/45dim/− CACs decreased following HII (21%, P < 0.05). TM and syndecan-1 increased with both exercise intensities (both ~20%, P < 0.05). HII, but not MOD, increased vWF (88%, P < 0.001), ci-miR-126–3p (92%, P = 0.009) and ci-miR-126–5p (110%, P = 0.01). The changes in several circulating factors correlated with changes in FMD following either one or both intensities. Changes in circulating factors do not support the concept of exercise-induced endothelial cell denudation, apoptosis, or activation, though slight disruption of endothelial glycocalyx and membrane integrity may occur. A related loss of mechanotransduction along with mechanisms underlying endothelial activation and ci-miR-126 secretion may relate to changes in endothelial function. NEW & NOTEWORTHY Using circulating endothelial-derived factors, we show that endothelial denudation, apoptosis, and activation do not appear to increase, whereas disrupted endothelial glycocalyx and membrane integrity may occur during both high-intensity interval and moderate intensity cycling. Increases in factors nonspecific to endothelial damage, including von Willebrand factor and microRNA-126, occurred only after high-intensity interval exercise. These results shed light on the hypothesis that disrupted endothelial integrity contributes to the endothelial function response to exercise.

Endogenous sex hormone concentrations vary between healthy naturally menstruating (non-OCP) and oral contraceptive pill-using (OCP) women, as well as across cycles. The aim of this study was to investigate potential differences in concentrations of inflammatory cytokine, interleukin-6 (IL-6), vasoconstrictive substance, endothelin-1 (ET-1), and measures of vascular function among relatively lower and higher hormone phases of non-OCP and OCP. Concentrations of estrogen, progesterone, IL-6 and ET-1 and measures of vascular function were collected in 22 women (22±1 y, OCP: n=12) during the early follicular (EF, ≤5 days of menstruation onset) and early luteal (EL, 4±2 days post-ovulation) phases of non-OCP and were compared to the placebo pill (PP, ≤5 days of PP onset) and active pill (AP, ≤5 days of highest dose AP) phases of OCP. Vascular function was assessed via brachial artery flow-mediated dilation (%FMD). Concentrations of endogenous estrogen and progesterone were higher in the EL phase as compared to the EF phase of non-OCP (p=0.01) but were similar between phases of OCP (p>0.05). IL-6 was higher in non-OCP during the EF phase as compared to the EL phase as well as compared to OCP during the PP phase (p=0.002) but was similar between groups during the EL and AP phases, respectively (p>0.05). Concentrations of ET-1 and measures of %FMD were similar between groups and unaffected by phase (p>0.05). Thus, there exists variation in inflammation between young, healthy non-OCP and OCP during the lower hormone phase, despite similarities in vascular function and concentrations of ET-1 between groups and phases.

Both aberrant vascular reactivity to acute cardiovascular stress and epigenetic mechanisms such as microRNA (miR) may underlie the increased propensity for African Americans (AA) to develop cardiovascular disease. This study assessed racial differences in acute induced endothelial inflammation and related miRs. Cultured human umbilical vein endothelial cells (HUVECs) derived from AA and Caucasian Americans (CA) were exposed to the influenza vaccine to determine changes in inflammatory markers, endothelial nitric oxide synthase (eNOS), and miR expression/release. Endothelial function (flow-mediated dilation [FMD]), circulating IL-6, and circulating miR were also measured in young, healthy AA and CA individuals before and after receiving the influenza vaccine. There were no significant racial differences in any parameters at baseline. The vaccine induced increases in IL-6 release (24%, P=0.02) and ICAM-1 mRNA (40%, P=0.03), as well as reduced eNOS mRNA (24%, P=0.04) in AA HUVECs, but not in CA HUVECs (all P>0.05). Intracellular levels of anti-inflammatory miR-221-3p and miR-222-3p increased specifically in CA HUVECs (72% and 53%, p=0.04 and p=0.06), while others did not change in either race. HUVEC secretion of several miRs decreased in both races, while the release of anti-inflammatory miR-150-5p was decreased only by AA cells (-30%, P=0.03). In individuals of both races, circulating IL-6 increased ~two-fold 24 hours after vaccination (both P<0.01) and returned to baseline levels by 48 hours, while FMD remained unchanged. Although macrovascular function was unaffected by acute inflammation in AA and CA individuals, AA endothelial cells exhibited increased susceptibility to acute inflammation and unique changes in related miR.

High-intensity interval (HII) exercise elicits distinct vascular responses compared to a matched dose of moderate intensity continuous (MOD) exercise. However, the acute effects of HII compared to MOD exercise on arterial stiffness are incompletely understood. Circulating microRNAs (ci-miRs) may contribute to the vascular effects of exercise. We sought to determine exercise intensity-dependent changes in ci-miR potentially underlying changes in arterial stiffness. Ten young, healthy men underwent well-matched, 30-min HII and MOD exercise bouts. RT-qPCR was used to determine the levels of seven vascular-related ci-miRs in serum obtained immediately before and after exercise. Arterial stiffness measures including carotid to femoral pulse wave velocity (cf-PWV), carotid arterial compliance and β-stiffness, and augmentation index (AIx and AIx75) were taken before, 10min after and 60min after exercise. Ci-miR-21-5p, 126-3p, 126-5p, 150-5p, 155-5p, and 181b-5p increased after HII exercise (p < .05), while ci-miR-150-5p and 221-3p increased after MOD exercise (p = .03 and 0.056). One hour after HII exercise, cf-PWV trended toward being lower compared to baseline (p = .056) and was significantly lower compared to 60min after MOD exercise (p = .04). Carotid arterial compliance was increased 60min after HII exercise (p = .049) and was greater than 60min after MOD exercise (p = .02). AIx75 increased 10 min after both HII and MOD exercise (p < .05).There were significant correlations between some of the exercise-induced changes in individual ci-miRs and changes in cf-PWV and AIx/AIx75. These results support the hypotheses that arterial stiffness and ci-miRs are altered in an exercise intensitydependent manner, and ci-miRs may contribute to changes in arterial stiffness.

Low serum total testosterone (TT) is associated with increased cardiovascular risk and metabolic derangements, with fatty liver (FL) emerging as an additional cardiometabolic threat. We investigated the associations between TT and cardiometabolic (CM) health in 298 US male firefighters. Cross-sectional data from occupational health examination were analyzed. TT was categorized as low (< 264 ng/dL), borderline (264–399 ng/dL), and reference (400–916 ng/dL). Conventional CM risk factors were compared among TT categories, and between firefighters with and without FL. 81% of firefighters were obese/overweight; almost 40% had FL. In the low-TT group, only 3.1% had normal BMI, while 78.1% had FL. The low-TT group had a worse CM profile, independently of age and BMI, and a fourfold higher adjusted odds of having FL. FL was associated with lower TT, regardless of age, BMI and HbA1c. Having a FL, HbA1c ≥ 5.7% or triglycerides ≥ 150 mg/dL increased the odds for low-TT by 4.1, 2.7 and 6.6 times, respectively. These real-world data reveal strong associations between low-TT and CM risk factors and support a call for action towards screening for low-TT and FL, regardless of age, BMI or dysmetabolic conditions in firefighters. Recognizing cardiometabolic risks in firefighters provides an opportunity to lessen cardiovascular diseases burden.

New Findings What is the central question of this study?Are there differences in blood pressure, arterial stiffness and indices of pressure waveforms between young oral contraceptive pill‐using and naturally menstruating women during lower and higher hormone phases of their cycles? What is the main finding and its importance?Blood pressure, arterial stiffness and indices of pressure waveforms are influenced similarly by exogenous and endogenous hormones. However, lower levels of exogenous hormones moderately increase blood pressure among oral contraceptive pill‐using women. Abstract Elevations in blood pressure (BP) are understood as having a bidirectional relationship with stiffening of central and peripheral arteries. Arterial stiffness is mitigated by oestrogen, which aides in arterial vasorelaxation. To evaluate whether BP, stiffness, and pressure waveforms were different between young healthy naturally menstruating (non‐OCP) and oral contraceptive pill (OCP)‐using women, we measured brachial and aortic BPs, carotid‐to‐femoral pulse wave velocity, carotid β‐stiffness, elastic modulus, central augmentation index and augmentation index normalized to a heart rate of 75 bpm, and forward and backward pressure waveforms in 22 women (22 (1) years, OCP: n = 12). To assess phasic differences, women were studied during the early follicular (≤5 days of menstruation onset) and early luteal (4 (2) days post‐ovulation) phases of non‐OCP and compared to the placebo pill (≤5 days of onset) and active pill (≤5 days of highest‐dose active pill) phases of OCP. During the lower hormone phases, OCP users had significantly higher brachial systolic blood pressure (SBP) (119.3 (8.3) vs. 110.2 (8.3) mmHg, P = 0.02) and aortic SBP (104.10 (7.44) vs. 96.80 (6.39) mmHg, P = 0.03) as compared to non‐OCP users; however, during the higher hormone phases, there were no differences in measures of brachial or aortic BP, arterial stiffness, or indices of BP waveforms between OCP and non‐OCP users (P ≥ 0.05). In conclusion, exogenous and endogenous hormones have similar influences on BP and arterial stiffness; however, lower levels of exogenous hormones augment both central and peripheral BPs.

Sex differences in cardiovascular disease incidence in premenopausal women and age-matched men have been attributed to the cardioprotective influence of oestrogen. However, limited knowledge exists regarding sex differences following acute inflammation when oestrogen concentrations are lower in women. We evaluated sex differences in vascular responses to induced inflammation when oestrogen concentrations are typically lower in women (early follicular phase or placebo phase of hormonal contraception). In 15 women and 14 men, interleukin-6 (IL-6) concentrations and vascular function [via brachial artery flow-mediated dilatation (FMD)] were assessed at baseline (BL) and 24 (24H) and 48 hours (48H) after administration of influenza vaccine. After induction of inflammation, both sexes exhibited an increase in IL-6 concentrations at 24H [mean (SD) BL vs. 24H: women, 0.563 (0.50) vs. 1.141 (0.65) pg/ml; men, 0.385 (0.17) vs. 1.113 (0.69) pg/ml; P < 0.05] that returned to near-baseline concentrations by 48H (BL vs. 48H, P > 0.05). There were no sex differences in FMD, allometrically scaled FMD or IL-6 concentrations at any time point (P > 0.05). Notably, women exhibited significantly lower microvascular function than men at every time point [P < 0.05; reactive hyperaemic area under the curve (in

Endogenous sex hormone concentrations vary across the menstrual cycle of naturally menstruating premenopausal women and may elicit concomitant changes in vascular function. Specifically, estrogen (E2) may enhance vascular function, partially by increasing nitric oxide bioavailability. In contrast, the influence of progesterone (P4) on vascular function remains unclear, with some data suggesting it increases nitric oxide bioavailability and other data suggesting it antagonizes the dilatory effects of E2. The objective of the study was to elucidate potential effects of P4 on the macrovascular function of healthy premenopausal women in the presence of relatively lower E2 concentrations. It was hypothesized that measures of macrovascular function would be similar between the early follicular (EF) and early luteal (EL) phases of healthy premenopausal women, despite a significant increase in the progesterone‐to‐estrogen ratio from the EF to the EL phase. Sex hormones and vascular function were measured in ten healthy premenopausal women (22±2 y) during the EF phase (within 5 days of the onset of menstruation) and the EL phase (4±2 days post‐ovulation) of a single menstrual cycle. Serum concentrations of E2 and P4 were analyzed using enzyme‐linked immunosorbent assays. Independent concentrations of E2 and P4 were calculated, as well as P4:E2. Macrovascular function was assessed via brachial artery flow‐mediated dilation (FMD). %FMD was calculated as the percent change in brachial artery diameter following an ischemic stimulus. Data were compared between phases with paired t‐tests. Serum concentrations of E2 and P4 increased from the EF to the EL phase (91.8±34.5 vs. 120.9±32.6 pg/mL, p=0.01 and 1.4±0.6 vs. 5.1±3.6 ng/mL, p=0.01, respectively). The P4:E2 increased significantly from the EF to the EL phase as a result of the P4 surge in the EL phase (15.5±4.8 vs. 42.9±30.5, p=0.02). %FMD did not differ between the EF and EL phases (9.6±4.4 vs. 9.5±3.5 %, p=0.97). In conclusion, the macrovascular function of healthy premenopausal women is similar between the EF and EL phases despite significant increases in the P4:E2. Findings may suggest that P4 does not play an antagonist role on E2 and may have a synergistic effect on increasing %FMD among decreased concentrations of E2.