Sex Differences In Blood Pressure Research Articles

Sex-Dependency of T Cell-Induced Salt-Sensitive Hypertension and Kidney Damage.

It is established that the immune system, namely T cells, plays a role in the development of hypertension and renal damage in male Dahl salt-sensitive (SS) rats, but far less is known about this relationship in females. Rats with genetically deleted T cells via CD247 gene mutation on the Dahl SS background (SSCD247-/-) were utilized to interrogate the effect of sex and T cells on salt sensitivity. We assessed the hypertensive and kidney injury phenotypes in male versus female SS and SSCD247-/- rats challenged with 3 weeks of high salt (4.0% NaCl). Differences in T-cell activation genes were examined in renal T cells from male and female SS rats, and a sex-specific adoptive transfer was performed by injecting male or female splenocytes into either male or female SSCD247-/- recipients to determine the potential contribution of T-cell sex. The lack of functional T cells in SSCD247-/- rats significantly reduced salt-induced hypertension and proteinuria in both sexes, although SSCD247-/- females exhibited greater protection from kidney damage. Adoptive transfer of either Dahl SS male or female splenocytes into SSCD247-/- male recipients exacerbated hypertension and proteinuria compared with controls, while in SSCD247-/- female recipients, exacerbation of disease occurred only upon transfer of male, but not female, SS splenocytes. The absence of T cells in the SSCD247-/- normalized sex differences in blood pressure, though sex differences in renal damage persisted. Splenocyte transfer experiments demonstrated that salt sensitivity is amplified if the sex of the T cell or the recipient is male.

An evolutionarily conserved olfactory receptor is required for sex differences in blood pressure.

Sex differences in blood pressure are well-established, with premenopausal women having lower blood pressure than men by ~10 millimeters of mercury; however, the underlying mechanisms are not fully understood. We report here that sex differences in blood pressure are absent in olfactory receptor 558 knockout (KO) mice. Olfr558 localizes to renin-positive cells in the kidney and to vascular smooth muscle cells. Female KOs exhibit increased blood pressure and increased pulse wave velocity. In contrast, male KO mice have decreased renin expression and activity, altered vascular reactivity, and decreased diastolic pressure. A rare OR51E1 (human ortholog) missense variant has a statistically significant sex interaction effect with diastolic blood pressure, increasing diastolic blood pressure in women but decreasing it in men. In summary, our findings demonstrate an evolutionarily conserved role for OLFR558/OR51E1 to mediate sex differences in blood pressure.

Sex-specific genetic architecture of blood pressure.

The genetic and genomic basis of sex differences in blood pressure (BP) traits remain unstudied at scale. Here, we conducted sex-stratified and combined-sex genome-wide association studies of BP traits using the UK Biobank resource, identifying 1,346 previously reported and 29 new BP trait-associated loci. Among associated loci, 412 were female-specific (Pfemale ≤ 5 × 10-8; Pmale > 5 × 10-8) and 142 were male-specific (Pmale ≤ 5 × 10-8; Pfemale > 5 × 10-8); these sex-specific loci were enriched for hormone-related transcription factors, in particular, estrogen receptor 1. Analyses of gene-by-sex interactions and sexually dimorphic effects identified four genomic regions, showing female-specific associations with diastolic BP or pulse pressure, including the chromosome 13q34-COL4A1/COL4A2 locus. Notably, female-specific pulse pressure-associated loci exhibited enriched acetylated histone H3 Lys27 modifications in arterial tissues and a female-specific association with fibromuscular dysplasia, a female-biased vascular disease; colocalization signals included Chr13q34: COL4A1/COL4A2, Chr9p21: CDKN2B-AS1 and Chr4q32.1: MAP9 regions. Sex-specific and sex-biased polygenic associations of BP traits were associated with multiple cardiovascular traits. These findings suggest potentially clinically significant and BP sex-specific pleiotropic effects on cardiovascular diseases.

Adjusting for muscle strength and body size attenuates sex differences in the exercise pressor reflex in young adults.

Females typically exhibit lower blood pressure (BP) during exercise than males. However, recent findings indicate that adjusting for maximal strength attenuates sex differences in BP during isometric handgrip (HG) exercise and postexercise ischemia (PEI; metaboreflex isolation). In addition, body size is associated with HG strength but its contribution to sex differences in exercising BP is less appreciated. Therefore, the purpose of this study was to determine whether adjusting for strength and body size would attenuate sex differences in BP during HG and PEI. We obtained beat-to-beat BP in 110 participants (36 females, 74 males) who completed 2 min of isometric HG exercise at 40% of their maximal voluntary contraction followed by 3 min of PEI. In a subset (11 females, 17 males), we collected muscle sympathetic nerve activity (MSNA). Statistical analyses included independent t tests and mixed models (sex × time) with covariate adjustment for 40% HG force, height2, and body surface area. Females exhibited a lower absolute 40% HG force than male participants (Ps < 0.001). Females exhibited lower Δsystolic, Δdiastolic, and Δmean BPs during HG and PEI than males (e.g., PEI, Δsystolic BP, 15 ± 11 vs. 23 ± 14 mmHg; P = 0.004). After covariate adjustment, sex differences in BP responses were attenuated. There were no sex differences in MSNA. In a smaller strength-matched cohort, there was no sex × time interactions for BP responses (e.g., PEI systolic BP, P = 0.539; diastolic BP, P = 0.758). Our data indicate that sex differences in exercising BP responses are attenuated after adjusting for muscle strength and body size.NEW & NOTEWORTHY When compared with young males, females typically exhibit lower blood pressure (BP) during exercise. Adjusting for maximal strength attenuates sex differences in BP during isometric handgrip (HG) exercise and postexercise ischemia (PEI), but the contribution of body size is unknown. Novel findings include adjustments for muscle strength and body size attenuate sex differences in BP reactivity during exercise and PEI, and sex differences in body size contribute to HG strength differences.

Cardiovascular responses to combined mechanoreflex and metaboreflex activation in healthy adults: effects of sex and low- versus high-hormone phases in females.

Females generally have smaller blood pressure (BP) responses to isolated muscle mechanoreflex and metaboreflex activation compared with males, which may explain sex differences in BP responses to voluntary exercise. The mechanoreflex may be sensitized during exercise, but whether mechanoreflex-metaboreflex interactions differ by sex or variations in sex hormones remains unknown. Thirty-one young healthy subjects (females, n = 16) performed unilateral passive cycling (mechanoreflex), active cycling (40% peak Watts), postexercise circulatory occlusion (PECO; metaboreflex), and passive cycling combined with PECO (combined mechanoreflex and metaboreflex activation). Beat-to-beat BP, heart rate, inactive leg vascular conductance, and active leg muscle oxygenation were measured. Ten females underwent exploratory testing during low- and high-hormone phases of their self-reported menstrual cycle or oral contraceptive use. Systolic BP and heart rate responses did not differ between sexes during active cycling [Δ30 ± 9 vs. 29 ± 11 mmHg (males vs. females), P = 0.9; Δ33 ± 8 vs. 35 ± 6 beats/min, P = 0.4] or passive cycling with PECO (Δ26 ± 11 vs. 21 ± 10 mmHg, P = 0.3; Δ14 ± 7 vs. 18 ± 15 beats/min, P = 0.3). Passive cycling with PECO revealed additive, not synergistic, effects for systolic BP [males: Δ23 ± 14 vs. 26 ± 11 mmHg (sum of isolated passive cycling and PECO vs. combined activation); females: Δ26 ± 11 vs. 21 ± 12 mmHg, interaction P = 0.05]. Results were consistent in subset analyses with sex differences in active cycling BP (P > 0.1) and exploratory analyses of hormone phase (P > 0.4). Despite a lack of statistical equivalence, no differences in cardiovascular responses were found during combined mechanoreflex-metaboreflex activation between sexes or hormone levels. These results provide preliminary data regarding the involvement of muscle mechanoreflex-metaboreflex interactions in mediating sex differences in voluntary exercise BP responses.NEW & NOTEWORTHY The muscle mechanoreflex may be sensitized by metabolites during exercise. We show that cardiovascular responses to combined mechanoreflex (passive cycling) and metaboreflex (postexercise circulatory occlusion) activation are primarily additive and do not differ between males and females, or across variations in sex hormones in females. Our findings provide new insight into the contributions of muscle mechanoreflex-metaboreflex interactions as a cause for prior reports that females have smaller blood pressure responses to voluntary exercise.

Abstract 008: Sex-dependency Of T Cell-induced Salt-sensitive Hypertension And Kidney Damage

We have previously demonstrated that female Dahl Salt-Sensitive (SS) rats are protected from salt-induced hypertension and renal injury compared to males. There is an immunological component to this sex difference, since genetic deletion of T cells via mutation of the CD247 gene on the Dahl SS genetic background (CD247-/-) normalizes sex differences in blood pressure, though females are still protected from salt-sensitive renal damage compared to males. The current study hypothesized that sex of the T cell is an important factor in determining the severity of salt-sensitivity. We tested the hypothesis via a sex-specific splenocyte transfer by freshly isolating 10 7 male or female splenocytes and injecting them i.p. on postnatal day 5 into either male or female CD247-/- recipients. At 9 weeks of age, rats underwent a 3 week high salt challenge (HS, 4.0% NaCl, AIN-76A), with blood pressure measured continuously by telemetry and overnight urine collected weekly to assess renal damage. All data presented are from HS day 21. Transfer of either male or female donor splenocytes into CD247-/- recipient males exacerbated salt-induced hypertension compared to PBS vehicle controls (+PBS: 143.7±2.9, +Male: 152.8±5.2, +Female: 151.8±3.9 mmHg, n=11-14, p&lt;0.05). Similarly reflected in proteinuria, splenocyte transfer, regardless of sex, also worsened kidney damage in male CD247-/- recipients (+PBS: 191.9±26.7, +Male: 304.6±51.3, +Female: 283.9±37.1 mg/day, n=12-16, p&lt;0.05). In CD247-/- female recipients, there was an exacerbation in blood pressure with the transfer of male splenocytes (+PBS: 144.8±6.1, +Male: 151.5±3.9 mmHg, n=6-13, p&lt;0.05), but no significant change with the transfer of female splenocytes (+Female: 145.3±2.6 mmHg). There was a trend for male splenocytes to worsen proteinuria in CD247-/- female recipients (+PBS: 103.9±11.1, +Male: 157.7±21.2 mg/day, n=6-14, p=0.056), but there was a significant reduction in the transfer of female versus male splenocytes (+Female: 113.2±15.7, p&lt;0.05). Through flow cytometry, we confirmed similar extent of T cell reconstitution in both male and female CD247-/- recipients. These data demonstrate that salt-sensitive hypertension and renal damage are amplified if the sex of the T cell or the recipient are male.

Acute nitric oxide synthase inhibition induces greater increases in blood pressure in female versus male Wistar Kyoto rats.

Nitric oxide (NO) contributes to blood pressure (BP) regulation via its vasodilatory and anti-inflammatory properties. We and others previously reported sex differences in BP in normotensive and hypertensive rat models where females have lower BP than age-matched males. As females are known to have greater NO bioavailability than age-matched males, the current study was designed to test the hypothesis that anesthetized female normotensive Wistar Kyoto rats (WKY) are more responsive to acute NOS inhibition-induced increases in BP compared to male WKY. Twelve-week-old male and female WKY were randomized to infusion of the nonspecific NOS inhibitor NG -nitro-L-arginine methyl ester (L-NAME, 1 mg/kg/min) or selective NOS1 inhibition with vinyl-L-NIO (VNIO, 0.5 mg/kg/min) for 60 min. Mean arterial BP, glomerular filtration rate (GFR), urine volume, and electrolyte excretion were assessed before, and during L-NAME or VNIO infusion. L-NAME and VNIO significantly increased BP in both sexes; however, the increase in BP with L-NAME infusion was greater in females versus males compared to baseline BP values. Acute infusion of neither L-NAME nor VNIO for 60 min altered GFR in either sex. However, urine volume, sodium, chloride and potassium excretion levels increased comparably in male and female WKY with L-NAME and VNIO infusion. Our findings suggest sex differences in BP responses to acute non-isoform-specific NOS inhibition in WKY, with females being more responsive to L-NAME-induced elevations in BP relative to male WKY. However, sex differences in the BP response did not coincide with sex differences in renal hemodynamic responses to acute NOS inhibition.

An Evolutionarily Conserved Olfactory Receptor Is Required for Sex Differences in Blood Pressure

Olfactory receptor 558 (Olfr558) is expressed in the kidney where its functional role is unknown. Using RNAScope, we find that Olfr558 localizes to vascular smooth muscle, including the renal afferent arteriole. Thus, we measured blood pressure (BP) in Olfr558 wild-type (WT) and knockout (KO) mice. Systolic (SBP), diastolic (DBP), and mean arterial pressure (MAP) were measured in whole-body Olfr558 wild-type (WT) and knockout (KO) via telemetry. It is known that males have a higher BP than premenopausal females in both humans and mice; indeed, we find Olfr558WT males (M) have higher BP than females (F, n=7-9 per group), including MAP (M:101.0±1.6 vs. F:89.0±0.9 mmHg, p&lt;0.0001), SBP (M:113±2 vs. F:102±1mmHg, p=0.0025), and DBP (M: 89±2 vs. F:75±01mmHg, p&lt;0.0001). However, sex differences in BP are entirely absent in Olfr558 KO (MAP M: 96±2 vs. F: 95±1mmHg; SBP M: 110±2 vs. F: 108±2mmHg; DBP M: 81±2 vs. F: 82±2mmHg). Of note, other sex differences (body weight) are intact in KO, and KO males and females are fertile. To characterize this phenotype, renin expression was analyzed by qPCR, plasma renin activity (PRA) was measured by ELISA, and vasoreactivity was examined ex vivo by wire myography (responses to potassium chloride (KCl), phenylephrine (PE), acetylcholine (Ach), and sodium nitroprusside (SNP) in aortic and mesenteric rings). In male KOs (n=10-12), there was a decrease in kidney renin mRNA (0.4±0.1 vs WT: 1±0.1 p=0.001) and PRA (201±21 vs WT: 402±15, p=0.001); these parameters were unchanged in female KOs. Male KO aortic rings exhibit less constriction to PE, male KO mesenterics exhibit more relaxation to SNP, and female KO aortic rings exhibit more constriction to KCl. In females, pulse wave velocity (PWV) and tensile testing revealed that KO females have increased PWV (KO: 4.6±0.4 vs WT: 3.2±0.2 m/s, p=0.0069, n=8-11), but no changes in tensile testing. The human ortholog of Olfr558, OR51E1, was previously identified as a locus associated with DBP. Using UK Biobank data (N~450k), we find that a rare OR51E1 missense variant has a statistically significant sex interaction effect with DBP ( p=0.015), increasing DBP (+6.28mmHg) in women but decreasing it (-4.77mmHg) in men (similar to the phenotype in M and F Olfr558 KO mice). Finally, we express OR51E1 variants in HEK 293T cells and characterize how two different clinically relevant OR51E1 variants influence OR51E1 signaling. In sum, our findings demonstrate that an evolutionarily conserved olfactory receptor is required for sex differences in BP. Olfr558 regulates BP in males via renin and vascular reactivity, but via arterial stiffness in females. Funding: R56DK107726 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

High-fat loading abolishes sex differences in blood pressure (BP) responses to high-salt in Dahl rats

There are numerous reports that male Dahl rats have greater increases in BP with a high-salt (HS) diet than females, yet women have been suggested to be more salt-sensitive than men. Since the typical Western diet consists of both HS and high-fat (HF), the goal of the present study was to test the hypothesis that HF loading and a combined HF/HS would abolish the protection observed in female Dahl rats vs. males. To test our hypothesis, 6 week old male and female Dahl rats were implanted with telemetry devices to continuously measure mean arterial BP; n=6. Rats were allowed to recover for one week followed by one week of baseline BP recording. Rats were then placed on a HF diet (60% kcal from lard; Bio-Serv) for 2 weeks followed by a HF/HS (4% salt; Bio-Serv) for an additional 2 weeks. Rats were placed in metabolic cages prior to starting HS and after 2 weeks to collect a 24 hour urine sample to measure urinary protein and albumin excretion. Glomerular filtration rate (GFR) was measured at the end of the study conscious freely moving animals using FITC-inulin elimination method. Baseline BP values were comparable between males (115±5 mmHg) and females (117±3 mmHg; p=0.67). BP increased during HF diet treatment, yet BP values remained similar in males and females (133±7 vs. 134±3 mmHg, respectively; p=0.93). Interestingly, females had a greater increase in BP on HF/HS vs. males that reached significance by the end of the study (146±7 vs. 160±6 mmHg, respectively; p=0.03). Despite this, urinary protein (185±23 vs. 94±19 mg/day; p=0.001) and albumin (142±22 vs. 56±13 mg/day; p=0.006) excretion were greater in males than in females. However, GFR was comparable between males and females (0.55 ± 0.03 vs. 0.45 ± 0.04 ml/min/100 g of body weight; p=0.07). In conclusion, female Dahl rats are not protected from HS diet when also challenged with HF, supporting our hypothesis that HF loading eliminates cardiovascular protection in females vs. males. However, males exhibited greater renal injury. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Corrigendum for: Sex Differences in Blood Pressure, Free Radicals and Plasma Cholesterol Fractions in Ren-2 Transgenic Rats of Various Ages.

List of changes: On the basis of author's request the publisher of Physiological Research decided to change the license of the article to CC BY license.

Sex differences in blood pressure and inactive limb blood flow responses during dynamic leg exercise with increased inspiratory muscle work.

We hypothesized that, compared with young males, young females have a smaller decrease in blood flow to the inactive limb, accompanied by a smaller increase in arterial blood pressure, during dynamic exercise with increased inspiratory muscle work. Young males and females performed dynamic knee-extension and -flexion exercises for 10 min (spontaneous breathing for 5 min and voluntary hyperpnoea with or without inspiratory resistance for 5 min). Mean arterial blood pressure (MAP) and mean blood flow (MBF) in the brachial artery were continuously measured by means of finger photoplethysmography and Doppler ultrasound, respectively. No sex differences were found in the ΔMAP and ΔMBF (Δ: from baseline) during exercise without inspiratory resistance. In contrast, the ΔMAP during exercise with inspiratory resistive breathing was greater (P < 0.05) in males (+31.3 ± 2.1 mmHg, mean ± SE) than females (+18.9 ± 3.2 mmHg). The MBF during exercise with inspiratory resistance did not change in males (-4.4 ± 10.6 mL/min), whereas it significantly increased in females (+25.2 ± 15.4 mL/min). These results suggest that an attenuated inspiratory muscle-induced metaboreflex in young females affects blood flow distribution during submaximal dynamic leg exercise.

Sex differences in apoptosis do not contribute to sex differences in blood pressure or renal T cells in spontaneously hypertensive rats.

Apoptosis is a physiological and anti-inflammatory form of cell death that is indispensable for normal physiology and homeostasis. Several studies have reported aberrant activation of apoptosis in various tissues at the onset of hypertension. However, the functional significance of apoptosis during essential hypertension remains largely undefined. The current study was designed to test the hypothesis that apoptosis contributes to sex differences in blood pressure and the T cell profile in spontaneously hypertensive rats (SHR). Apoptosis was measured in kidney, aorta and spleen of 13-week-old adult hypertensive male and female SHR. Female SHR had greater renal and aortic apoptosis compared to age-matched males; apoptosis in the spleen was comparable between the sexes. Based on well-established sex differences in hypertension, we tested the hypothesis that greater apoptosis in female SHR contributes to the lower BP and pro-inflammatory profile compared to males. Male and female SHR were randomized to receive vehicle or ZVAD-FMK, a cell permeable pan-caspase inhibitor, in established hypertension from 13 to 15 weeks of age or at the onset of hypertension from 6 to 12 weeks or age. Treatment with ZVAD-FMK lowered renal apoptosis in both studies, yet neither BP nor renal T cells were altered in either male or female SHR. These results suggest that apoptosis does not contribute to the control or maintenance of BP in male or female SHR or sex differences in renal T cells.

Adjusting For Exercise Intensity Attenuates Sex Differences In Blood Pressure During Exercise In Healthy Adults

PURPOSE: The exercise pressor reflex, composed of the muscle mechano- and metaboreflex, increases blood pressure (BP). Compared to males, healthy female adults typically exhibit blunted BP responses to exercise. However, recent work suggests that sex differences in BP during isometric handgrip (HG) exercise and post-exercise ischemia (PEI; metaboreflex isolation) are attenuated after adjusting for differences in maximal voluntary contraction (MVC). Therefore, the purpose of this study was to determine whether sex differences in BP responses during HG and PEI would be attenuated after adjustment for submaximal HG squeezing force. METHODS: We analyzed data from 95 participants including 34 females (age: 24±4 years, BMI: 24±4 kg/m2, screening BP: 106±13/64±9 mmHg, Mean ± SD) and 61 males (age: 25±5 years, BMI: 2±3 kg/m2, screening BP: 113±11/66±9 mmHg). All females were tested during days 1-5 of their menstrual cycle. Maximal HG force for each participant was defined as the average of three MVCs. Following a 10-minute baseline period, participants performed static static HG exercise at 40% of their average MVC for two minutes followed by three minutes of PEI via brachial occlusion. We obtained beat-to-beat BP readings via finger photoplethysmography (Finometer). Statistical analyses included t-tests, 2-way ANOVAs (sex x time), and ANCOVAs (average HG force as a covariate). RESULTS: Females exhibited a lower absolute 40% HG force than males (105±30 N v. 169±45 N, p<0.001). There was a significant sex x time interaction for ∆ systolic BP during HG (e.g., minute 2, females: 20±12 mmHg v. 28±18 mmHg in males, p=0.014), but not ∆ diastolic (p=0.106) or ∆ mean BP (p=0.058). After adjusting for absolute HG force, the sex difference for peak ∆ systolic BP during HG was attenuated (p=0.072). During PEI there were sex x time interactions for ∆ systolic, ∆ diastolic, and ∆ mean BP (p<0.05 for all) and adjustment for HG force did not attenuate these differences. Additionally, in a small strength-matched cohort (N=48, 29 females, female HG force mean = 107±23 N, male HG force mean = 118 ± 24 N, p=0.092) there was not a significant sex difference for peak ∆ systolic BP during HG (p=0.667) or PEI (p=0.828). CONCLUSIONS: Our data indicate that the sex difference in BP reactivity is attenuated after adjusting for absolute HG force during exercise.

Sex Differences in Blood Pressure and Potential Implications for Cardiovascular Risk Management.

Accurate blood pressure (BP) measurement is critical for optimal cardiovascular risk management. Age-related trajectories for cuff-measured BP accelerate faster in women compared with men, but whether cuff BP represents the intraarterial (invasive) aortic BP is unknown. This study aimed to determine the sex differences between cuff BP, invasive aortic BP, and the difference between the 2 measurements. Upper-arm cuff BP and invasive aortic BP were measured during coronary angiography in 1615 subjects from the Invasive Blood Pressure Consortium Database. This analysis comprised 22 different cuff BP devices from 28 studies. Subjects were 64±11 years (range 40-89) and 32% women. For the same cuff systolic BP (SBP), invasive aortic SBP was 4.4 mm Hg higher in women compared with men. Cuff and invasive aortic SBP were higher in women compared with men, but the sex difference was more pronounced from invasive aortic SBP, was the lowest in younger ages, and the highest in older ages. Cuff diastolic blood pressure overestimated invasive diastolic blood pressure in both sexes. For cuff and invasive diastolic blood pressure separately, there were sex*age interactions in which diastolic blood pressure was higher in younger men and lower in older men, compared with women. Cuff pulse pressure underestimated invasive aortic pulse pressure in excess of 10 mm Hg for both sexes in older age. For the same cuff SBP, invasive aortic SBP was higher in women compared with men. How this translates to cardiovascular risk prediction needs to be determined, but women may be at higher BP-related risk than estimated by cuff measurements.

Sex differences in vascular aging and impact of GPER deletion.

Aging is a nonmodifiable risk factor for cardiovascular disease associated with arterial stiffening and endothelial dysfunction. We hypothesized that sex differences exist in vascular aging processes and would be attenuated by global deletion of the G protein-coupled estrogen receptor. Blood pressure was measured by tail-cuff plethysmography, pulse wave velocity (PWV) and echocardiography were assessed with high-resolution ultrasound, and small vessel reactivity was measured using wire myography in adult (25 wk) and middle-aged (57 wk) male and female mice. Adult female mice displayed lower blood pressure and PWV, but this sex difference was absent in middle-aged mice. Aging significantly increased PWV but not blood pressure in both sexes. Adult female carotids were more distensible than males, but this sex difference was lost during aging. Acetylcholine-induced relaxation was greater in female than male mice at both ages, and only males showed aging-induced changes in cardiac hypertrophy and function. GPER deletion removed the sex difference in PWV and ex vivo stiffness in adult mice. The sex difference in blood pressure was absent in KO mice and was associated with endothelial dysfunction in females. These findings indicate that the impact of aging on arterial stiffening and endothelial function is not the same in male and female mice. Moreover, nongenomic estrogen signaling through GPER impacted vascular phenotype differently in male and female mice. Delineating sex differences in vascular changes during healthy aging is an important first step in improving early detection and sex-specific treatments in our aging population.NEW & NOTEWORTHY Indices of vascular aging were different in male and female mice. Sex differences in pulse wave velocity, blood pressure, and large artery stiffness were abrogated in middle-aged mice, but the female advantage in resistance artery vasodilator function was maintained. GPER deletion abrogated these sex differences and significantly reduced endothelial function in adult female mice. Additional studies are needed to characterize sex differences in vascular aging to personalize early detection and treatment for vascular diseases.

Sex Differences in Blood Pressure—A Measured Relook at Measures

Yasmine Abbaoui; Catherine Fortier, PhD; Louis-Charles Desbiens, MD, MSc; Cédric Kowalski, MD; Florence Lamarche, MD, MSc; Annie-Claire Nadeau-Fredette, MD, MSc; François Madore, MD; Mohsen Agharazii, MD; Rémi Goupil, MD, MSc

Sex Differences in Temporal Trends of Cardiovascular Health in Young US Adults.

BackgroundFavorable cardiovascular health (CVH) in young adulthood has been associated with lower future cardiovascular risk. We determined whether CVH and its sex differences in young adults have changed from 2007 to 2018.Methods and ResultsWe identified 10 206 individuals, aged 20 to 39 years, from the National Health Examination and Nutrition Survey data. CVH was assessed on the basis of the American Heart Association’s Life’s Simple 7 metrics (of 7). Changes in the mean number of ideal CVH components and the ideal proportion of individual components were calculated using linear regression analysis. Changes in sex difference trends were assessed with an interaction term between sex and calendar year. The mean (SD) age of the study population was 29.3 (5.8) years, and 5260 (51.5%) individuals were women. The mean (SD) ideal CVH component remained unchanged for both women (4.40 [1.22] to 4.48 [1.15]; P=0.94) and men (3.97 [1.27] to 3.93 [1.24]; P=0.87), with stable sex differences (P for interaction=0.94). Nonetheless, sex differences in blood pressure widened as ideal blood pressure decreased in men (54.0% to 46.9%; P=0.03) but not in women (P for interaction <0.001). Concurrently, the proportion with ideal physical activity declined in women (57.3% to 49.4%; P=0.04) but remained stable in men (P for interaction=0.03). Nonsmoking increased to a greater extent in women (64.1% to 70.5%; P=0.05) than in men (P for interaction=0.01).ConclusionsSex disparities in CVH have persisted with exacerbated differences in blood pressure, physical activity, and smoking. These insights provide opportunities to promote equitable CVH.

Sex difference in blood pressure response to orthostatic stress: effects of transcutaneous electrical nerve stimulation.

We investigated sex differences in blood pressure (BP) response to transcutaneous electrical nerve stimulation (TENS) during orthostatic stress (ORT). Seventeen healthy young adults (males = 9; females = 8) underwent TENS or SHAM stimulus applied in the cervicothoracic region for 30 min in the supine position followed by 10 min in the orthostatic position. Electrocardiogram and BP were continuously recorded at rest and during ORT. Stroke volume (SV), cardiac output (CO) and total peripheral resistance (TPR) were calculated from the BP signal. Orthostatic challenge decreased BP similarly for both sexes during ORT, a deeper drop in CO and a slight increase in heart rate were found in women compared with men ( P = 0.03 and 0.05, respectively). TENS evoked a pronounced fall in SBP in men compared with the SHAM condition ( P < 0.05). TENS has no effect on SBP in women compared with the SHAM condition. This finding suggests a possible modulatory effect by one cervicothoracic TENS session on sympathetic tonus in healthy men.

Sex Differences in Insulin Sensitivity and Glomerular Function in African Green Monkeys

In the United States, it is estimated that approximately 10.5% of the population has diabetes of which 90% are classified as insulin resistant expressing Type 2 Diabetes Mellitus (T2DM). T2DM is one of the leading causes of end stage renal disease (ESRD) accounting for approximately 40% of new ESRD cases. Previous studies have reported a more prevalent decrease in renal function in glucose intolerant males when compared to pre‐menopausal females. Males also have been reported to have earlier onset and higher prevalence of T2DM compared to pre‐menopausal females. Renal injury can be present before the onset of T2DM however, sex differences in renal injury have yet to be assessed in humans. A subpopulation of African Green Monkeys (AGM; Chlorocebus aethiops sabaeus) in the Caribbean exhibit spontaneous glucose intolerance and co‐morbidities such as insulin insensitivity, and hypertension. The AGM also shares similar genomic expression and metabolic phenotypes to humans making them optimal for translatable diabetes research. We hypothesize that female AGM are protected against renal injury and early onset T2DM. Systolic blood pressure (SBP) was measured by forearm plethysmography. Glucose tolerance was assessed via conscious and anesthetized oral glucose tolerance tests (OGTT). All AGM were fasted 12‐18 hours prior to study with water provided ad libitum. Blood glucose was measured at 0, 15, 30, 60, 90, and 120 min after an oral glucose load. Conscious AGM OGTT were delivered as 0.75g glucose/kg body weight. Sedated AGM (ketamine, 15mg/kg, i.m.), received 5g/dl glucose and 15 ml/kg in water by oral gavage. Venous blood samples were collected at timepoints 0, 30, 60, and 120 minutes post glucose administration. Urine samples were collected for 3 days post OGTT. Kidney histology was performed by staining 10µm sections with Periodic‐Acid Schiff stain (PAS). A minimum of 10 glomeruli were identified at 400x magnification per animal then analyzed with ImageJ. There were no differences between lightly sedated or conscious OGTT. All AGM in this study were normotensive and there were no sex differences in blood pressure between male and female AGM (F=11; 113.9±3.73 mmHg, M=6; 117.6 ± 6.3mmHg). Female AGM OGTT area under the curve (AUC) over 120 minutes post glucose load were lower compared to male AGM (F; 11,961.5± 710.6 min x mg/dl, M; 14,076.3±710.6 min x mg/dl, p&lt;0.05). There were no significant differences in plasma insulin at all time points between male and female AGM (F; 2,013± 1,007 min x mIU/L, M; 5,940± 1,424.6 min x mIU/L) despite the lower glucose AUC in females. Renal glomerular function was assessed by measuring plasma creatinine, urinary albumin, and urinary albumin to creatinine ratio (UACR). Plasma creatinine was not different between male and females (F; 1.35±0.2 mg/dl, M; 1.77±0.25 mg/dl). Microalbuminuria was present in both male and female AGMs, in the absence of sex differences (F; 98.43±23.1 ng/ml, M; 81.15±29.2 ng/ml). UACRs were not different between male and female AGM. Glomerular injury was assessed by determining the intensity of glomerular PAS stain. PAS stain intensity was not different in male and female AGM (F=3; 178.3 ± 8.6, M=3; 181.6± 8.6) regardless of OGTT sensitivity. Together these data suggest that female AGM are more insulin sensitive than male AGM and may be protected against early onset T2DM. Despite differences in OGTT in male and female AGM, microalbuminuria suggested onset of renal dysfunction. We conclude that the AGM provides a strong nonhuman primate model of T2DM for the long‐term study of sex differences in the mechanisms of ESRD.

Sex differences in TLR4 expression in SHR do not contribute to sex differences in blood pressure or the renal T cell profile.

Hypertension is a primary risk factor for the development of cardiovascular disease. Mechanisms controlling blood pressure (BP) in men and women are still being investigated; however, there is increasing evidence supporting a role for the innate immune system. Specifically, Toll-like receptors (TLRs), and TLR4 in particular, have been implicated in the development of hypertension in male spontaneously hypertensive rats (SHR). Despite established sex differences in BP control and inflammatory markers in hypertensive males and females, little is known regarding the role of TLR4 in hypertension in females. Our hypotheses were that male SHR have greater TLR4 expression compared with females, and that sex differences in TLR4 contribute to sex differences in BP and the T cell profile. To test these hypotheses, initial studies measured renal TLR4 protein expression in 13-wk-old male and female SHR. Additional SHR were implanted with telemetry devices and randomized to treatment with either IgG or TLR4 neutralizing antibodies. Untreated control male SHR have greater TLR4 protein expression in the kidney compared with females. However, treatment with TLR4 neutralizing antibody for 2 wk did not significantly alter BP in either male or female SHR. Interestingly, neutralization of TLR4 increased renal CD3+ T cells in female SHR, with no alteration in CD4+ T cells or CD8+ T cells in either sex. Taken together, our data indicate that although male SHR have greater renal TLR4 expression than females, TLR4 does not contribute to the higher BP and more proinflammatory renal T cell profile in males versus females.