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.

Cerebral hemodynamics and pulsatility are important mechanisms of cerebrovascular and brain health. Cardiorespiratory fitness may improve cerebrovascular pulsatility in healthy females, but not males. Whether cardiovascular disease (CVD) risk factors modify sex-specific associations of fitness with cerebral hemodynamics and vascular contributors to cerebral hemodynamics is unknown. We assessed VO2peak and cerebrovascular hemodynamics in 157 adults without (42±13yrs, BMI 24.5±2.7kg/m2), and 66 adults with modifiable CVD risk factors (54±8yrs, BMI 29.9±4.0kg/m2). Intracranial (middle cerebral artery [MCA] pulsatility index [PI], mean velocity, conductance, pulsatile damping) and extracranial hemodynamics (carotid artery wave transmission/reflection, PI, pulse wave velocity [PWV]-β; carotid-femoral PWV) were assessed via transcranial Doppler/ultrasound and tonometry. Cardiorespiratory fitness was assessed via VO2peak during an incremental exercise test. Multiple regression was used to assess contributions of VO2peak to cerebrovascular outcomes after adjustment for relevant covariates. VO2peak was inversely associated with MCA PI among females (β=-0.39, p=0.01) but not males (β=-0.16, p=0.25) without CVD risk factors. VO2peak was positively associated with MCA PI among females (β=0.44, p=0.01) and not associated in males with CVD risk factors (β=-0.06, p=0.079). VO2peak was beneficially associated with vascular contributors to cerebral hemodynamics, but had sex-specific associations with carotid stiffness and pulse pressure in females without CVD risk factors only. These results suggest sex-specific associations between fitness and cerebral pulsatility among females without CVD risk factors may relate to the differential effects of fitness on carotid stiffness and pulse pressure. Additionally, presence of modifiable CVD risk factors may influence the protective relations of fitness on cerebrovascular hemodynamics.

Hypertension (HTN) affects more than one-third of the US population and remains the top risk factor for the development of cardiovascular disease (CVD). Identifying the underlying mechanisms for developing HTN are of critical importance because the risk of developing CVD doubles with ∼20 mmHg increase in systolic blood pressure (BP). Endothelial dysfunction, especially in the resistance arteries, is the primary site for initiation of sub-clinical HTN. Furthermore, inflammation and reactive oxygen and nitrogen species (ROS/RNS) not only influence the endothelium independently, but also have a synergistic influence on each other. Together, the interplay between inflammation, ROS and vascular dysfunction is referred to as the vascular health triad, and affects BP regulation in humans. While the interplay of the vascular health triad is well established, new underlying mechanistic targets are under investigation, including: Inducible nitric oxide synthase, hydrogen peroxide, hydrogen sulfide, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and nuclear factor activated T cells. This review outlines the role of these unusual suspects in vascular health and function in humans. This review connects the dots using these unusual suspects underlying inflammation, ROS and vascular dysfunction especially in individuals at risk of or with diagnosed HTN based on novel studies performed in humans.

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.

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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.