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.

Investigating the Influence of Sex Hormones on OLFR558

Premenopausal women have blood pressure that is ~10mmHg lower than age-matched men. Women incur cardiovascular disease risk at lower blood pressures than men, implying that this sex difference in blood pressure is functionally important; however, clinical management of blood pressure is identical in men and women (Ji et al Circulation 2021). Recently, a study from our lab examined an olfactory receptor (OLFR558) that is expressed in renal juxtaglomerular cells, as well as in all renal blood vessels and a subset of extrarenal blood vessels. We find that OLFR558 is required for sex differences in blood pressure, as sex differences in blood pressure are entirely absent in Olfr558 knockout mice (Xu et al BioRxiv 2022). However, there is a gap in our knowledge regarding how OLFR558 influences blood pressure, and, in the mechanism underlying the blood pressure differences between the sexes. We hypothesize that sex hormones act to modulate OLFR558 signaling. To pursue this, we examined whether sex hormones may act as agonists or antagonists of OLFR558; in parallel, we also examined the human ortholog of OLFR558 (OR51E1). Green Up cADDis cyclic AMP assays were performed (olfactory receptors elevate cAMP upon activation) in technical triplicates, and each experiment was repeated four times. A known agonist (butyrate) activated OLFR558 at 0.5mM (0.175±0.035 cAMP production ± SD), 1mM (0.208±0.038), 2mM (0.264±0.014) and 5mM (0.238±0.028) vs baseline (0.061±0.009); all comparisons significant vs baseline by one-way ANOVA, p<0.0001. We first tested estrone (E1), estradiol (E2), estriol (E3), progesterone (P), testosterone (T), follicle stimulating hormone (FSH), and luteinizing hormone (LH) as potential agonists for OLFR558. We find that none of these compounds activate OLFR558 (p values vs baseline/PBS: 50 nM estrogen: E1, p>0.999; E2, p=0.999; E3, p=0.938 35nM T: p>0.999, 50 nM P: p>0.999, 10 mIU FSH: p=0.9348, 100 mIU FSH: p-value=0.8429, 10 mIU LH: p value >0.999, 56 mIU LH: p value> 0.999). We then tested these compounds as potential antagonists for OLFR558 by measuring cAMP responses to butyrate in the presence of each hormone. Estrogen, P, and T were tested at two different butyrate doses (0.1mM and 0.2 mM), and LH and FSH were tested at four different butyrate doses (0.5mM, 1mM, 2mM, and 5mM). We find that estrogen and T do not act as antagonists (p-value vs. matched doses of butyrate alone are 0.650-0.725 for 50 nM estrogen, 0.625-0.653 for 50 nM P and 0.708-0.883 for 35 nM T). Similarly, we find that LH and FSH do not antagonize OLFR558 at any of the four butyrate doses tested (p value for hormone+butyrate vs. matched doses of butyrate alone is p-value 0.4275-0.9069 for 10 mIU LH, p-value 0.5225-0.9921 for 56mIU LH, p-value 0.1235-0.9732 for 10mIU FSH, and p-value 0.5610-0.9358 for 100 mIU FSH). Similarly, we find that the human ortholog OR51E1 is significantly activated by known ligand butyrate (0.5 mM: 0.176± 0.011 cAMP production ± SD, 1mM: 0.225±0.001, 2mM: 0.242±0.027, 5mM:0.249±0.021 versus baseline 0.087±0.003 by one-way ANOVA, p<0.0001), but is neither agonized nor antagonized by estrogen, P, T, LH or FSH. Looking ahead, we plan to investigate additional sex hormones and related metabolites, as well as alternative explanations for the phenotype. Better understanding of the relationship between sex hormones, blood pressure, and OLFR558/OR51E1 is pertinent to how physicians treat elevated blood pressure in men and women. Funding: American Heart Association Established Investigator Award (to JLP) and R21AG081683 (to JLP). ADM is supported by NIH PREP grant R25GM109441. This is the full abstract presented at the American Physiology Summit 2024 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.

Renal Oxidative Stress May Explain Sex Differences in Blood Pressure in Adult Offspring Exposed to an Impoverished Environment

Background: Nearly 40 million people experience poverty in the United States. Poverty is linked to adverse childhood experiences (ACEs) which affects about 64% of adults in the U.S. Previous studies indicate that those who experience ACEs are at a higher risk of developing hypertension (HTN) and cardiovascular diseases (CVDs) later in life, with a greater severity and earlier onset in males. The mechanisms behind the ACEs-attributed development of sex differences in HTN later in life is unknown. One plausible mechanism for this sex difference is increased oxidative stress. One rodent model to mimic poverty as an ACE is the limited bed and nesting (LBN) model. This model simulates an impoverished and low resource environment, as observed in poverty, in which the nesting material during weaning is reduced. We hypothesize that male offspring exposed to LBN will have elevated blood pressure and oxidative stress, while females will have no change in blood pressure and reduced oxidative stress. Methods: Pregnant Sprague Dawley rats gave birth naturally and weaned their offspring for 3 weeks. During the weaning period, on Days 2-9, the dams and their respective pups were divided into 2 groups: LBN and control (CON). After LBN treatment, all rats received normal bedding. After weaning, offspring were divided by sex and experimental status: LBN male (n=5), LBN female (n=5), CON male (n=6), and CON female (n=6). At 16-17 weeks, mean arterial pressure (MAP) was measured via carotid catheterization and the kidneys, brain, heart, and plasma were collected to measure antioxidant capacity via colorimetric biochemical assays. Results: LBN males had a significant increase (18 mmHg) in MAP compared to CON males (128.17±3.93 vs 110.72± 3.93 mmHg, P>0.001), while female LBN and CON rodents displayed no differences. In males, there were no changes in antioxidant capacity in the brain, heart, and plasma. However, there was a significant 2-fold decrease in renal antioxidant capacity (233±14.0 vs 442±12.3 mM Trolox/mg protein, p>0.0001). In females, there were no changes in the kidneys, heart, and brain antioxidant capacity. Conversely, LBN females showed a trending increase in plasma antioxidant capacity compared to CON (3.33±0.16 vs 2.53±0.35 mM Trolox/mg protein, p=0.053). Conclusion: Only males exposed to an impoverished environment during weaning have elevated blood pressure, while females do not. This difference in blood pressure may be explained by decreases in renal antioxidant capacity in males only. On the other hand, females may be protected from elevated blood pressure because they experience a slight increase in systemic antioxidant capacity. Future studies will examine the role of antioxidants in blood pressure regulation in the kidneys. This study is clinically relevant because ACEs affect a large percentage of the American population with about 17% of adults experiencing 4 or more ACEs, with minorities at a greater risk. Understanding the mechanisms on how ACEs contribute to HTN may alleviate some of the racial and ethnic disparities, along with the financial burden on the healthcare system to care for people with HTN and CVDs. Perhaps, organ and sex-specific antioxidant therapies may be used to alter, prevent, or reduce the development of HTN in adults that were exposed to ACEs, such as poverty during nursing and early childhood. This research was supported by start-up funds and the American Heart Association Early Career Development Award [AHA 18CDA34110264 (Cunningham)]. This is the full abstract presented at the American Physiology Summit 2024 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.

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.