Arterial hypertension is the most important modifiable cardiovascular risk factor and a major cause of cardiovascular mortality worldwide. In daily clinical practice, the hypertensive patient is often treated in a uniform way, thus ignoring the significant effects of sex on several aspects of hypertension, including its prevalence, pathophysiology, response to antihypertensive treatment, and outcomes. Along with the immune response and several cardiometabolic risk factors that frequently coexist, the substantial hormonal changes during a woman's life cycle are among the main pathophysiological mechanisms driving hypertension in women. Concurrently, women exhibit increased cardiovascular risk at lower blood pressure (BP) levels compared to age-matched men and present certain disparities in the incidence of cardiovascular events and subsequent hypertension-related cardiovascular prognosis. In addition, women respond differently to antihypertensive treatment, experience more drug-related side effects, and exhibit lower rates of BP control compared to men. Currently, international guidelines propose the same targets and the same therapeutic algorithms for the treatment of hypertension in both sexes without taking into account the sex differences that exist. In this review, we aim to describe certain particularities of arterial hypertension in the female sex, moving from pathophysiological aspects to clinical and therapeutical management.

Cancer-associated cachexia (CAC), also known as wasting syndrome, is a systemic condition that affects multiple tissues and organs via a variety of metabolic pathways. Systemic inflammation, progressive weight loss, depletion of adipose tissue, and skeletal muscle impairment are some of the hallmark features of cachexia. Despite various studies on the clinical features of CAC, the complexity of the syndrome continues to pose significant challenges in clinical practice, leading to late diagnoses and the absence of a standardised treatment. Men and women respond differently to CAC, which may be prompted by the pre-existing physiologic sex differences. This review presents the sexual dimorphism associated with the hallmark pathways involved in CAC. A comprehensive understanding of sexual dimorphism in these pathways could drive research on cachexia to prioritise the inclusion of more females in related studies in order to achieve personalised sex-based therapeutic approaches and, consequently, enhance treatment efficacy and better patient outcomes.

This study aimed to investigate the relationship between total antioxidant capacity (TAC) and phenotypic age acceleration (PhenoAgeAccel), a measure of accelerated biological aging, using data from the National Health and Nutrition Examination Survey (NHANES). Data from the 2003-2010 NHANES surveys, encompassing 16,395 participants, were analyzed. Principal component analysis (PCA) was used to reduce data dimensionality. Multivariate logistic regression models were employed to evaluate the association between TAC and antioxidant vitamins (α-carotene, β-carotene, β-cryptoxanthin, lycopene, lutein-zeaxanthin, vitamin A, vitamin C, vitamin E) with PhenoAgeAccel, adjusting for demographic, lifestyle, and clinical factors. Smoothed curve fitting and threshold effects analysis were conducted to explore the nonlinear relationship between log-transformed TAC and PhenoAgeAccel. Subgroup analyses were performed to assess potential effect modifiers based on age, gender, race, education, smoking, alcohol use, diabetes, hypertension, and hyperlipidemia. The weak correlations between the original variables prevent PCA from effectively capturing the primary variability within the data. Higher TAC was significantly inversely associated with PhenoAgeAccel in both unadjusted and adjusted models. Participants in the second tertile (T2) of TAC exhibited 11% lower odds of PhenoAgeAccel compared to those in the first tertile (T1) (OR = 0.89, 95% CI: 0.81-0.98, P = 0.0176). Intake of several antioxidant vitamins, including α-carotene, β-carotene, lutein-zeaxanthin, vitamin A, vitamin C, and vitamin E, was also inversely associated with the odds of PhenoAgeAccel. A nonlinear relationship between log-transformed TAC and PhenoAgeAccel was observed, with a significant protective effect within a specific range of TAC. Subgroup analyses revealed no significant effect modification by most factors, except for gender, smoking, and alcohol consumption. TAC is closely associated with PhenoAgeAccel. A nonlinear relationship was observed, with higher TAC exhibiting significant protective effects within a specific range, particularly among males, smokers, and alcohol consumer. These findings underscore the potential value of TAC in mitigating the aging process.

Inflammation and endothelial apoptosis are implicated in the advancement of atherosclerosis. EEPD1 holds a pivotal position in the repair of DNA damage and contributes to the progression of multiple cancers. However, the role of EEPD1 in cardiovascular diseases needs to be explored further, especially in atherosclerosis.

We constructed EEPD1 and ApoE (apolipoprotein E)-deficient mice to assess how EEPD1 influences endothelial inflammation and apoptosis within atherosclerotic plaques. High-throughput RNA sequencing of human aortic endothelial cell groups treated with siCon+TNFα and siEEPD1+TNFα identified notable disparities in the MAPK pathway between groups. Chromatin immunoprecipitation and luciferase reporter assay confirmed that KLF4 directly regulates EEPD1.

Further examination of gene expression data revealed elevated EEPD1 concentrations in atherosclerotic plaques of patients, which findings were corroborated in the aortas of ApoE-/- mice. Present study demonstrated that adhesion molecule expression, endothelial apoptosis, aortic root plaques and macrophage accumulation were markedly ameliorated in EEPD1-/-ApoE-/- mice compared to WT ApoE-/- mice. Functional analysis revealed that increase in EEPD1 promotes ERK phosphorylation and significantly increases endothelial apoptosis and inflammation in atherosclerosis, which was abrogated by inhibition of ERK phosphorylation. We found KLF4 to be the transcription repressor of EEPD1 through luciferase assay and chromatin immunoprecipitation, and KLF4 inhibition abrogated the amelioration of endothelial apoptosis and inflammation caused by EEPD1 deletion.

Collectively, this study revealed that EEPD1 deletion can lead to amelioration of atherosclerosis through the KLF4-EEPD1-ERK axis. Hence, targeting EEPD1 could be a promising therapeutic strategy for patients with atherosclerosis.

Menopause is associated with reduced nitric oxide (NO) bioavailability, a key contributor to increased arterial stiffness and, consequently, greater risk of cardiovascular disease-related mortality in postmenopausal females. Even though dietary nitrate has been shown to increase NO bioavailability in postmenopausal females acutely, previous studies showed no impact of dietary nitrate supplementation on arterial stiffness in postmenopausal females. Their findings were likely limited by the acute and/or short-term design. Thus, this study aimed to determine whether 12 wk of dietary nitrate supplementation via beetroot extract improves carotid artery stiffness in postmenopausal females. A randomized, double-blind, placebo-controlled, and parallel-design trial was conducted with 20 postmenopausal females (60-85 yr). Participants received nitrate-rich (NR-BEETx, 8.8 mmol/day) or nitrate-depleted (ND-BEETx) beetroot extract. Carotid stiffness parameters-pulse wave velocity (PWVβ), β stiffness, pressure-strain elastic modulus, augmentation index (AIx), and arterial compliance-were measured at baseline and weeks 4, 8, and 12. Serum nitrate and nitrite concentrations and blood pressure were also assessed. Compared with ND-BEETx, NR-BEETx supplementation significantly reduced PWVβ, β stiffness, elastic modulus, and AIx at weeks 4, 8, and 12, whereas arterial compliance increased by week 12. Serum nitrate and nitrite concentrations were elevated five- to sixfold and 1.5- to 2-fold, respectively, in the NR-BEETx group, with peak concentrations occurring at week 8 and showing a plateau or slight decrease at week 12. Blood pressure remained unchanged in both groups. Twelve weeks of nitrate-rich beetroot extract supplementation improved carotid artery stiffness and increased NO bioavailability without altering blood pressure. These findings suggest that beetroot extract supplementation can be recommended as an alternative nutritional strategy to mitigate carotid artery stiffening in postmenopausal females.NEW & NOTEWORTHY Postmenopausal females experience reduced nitric oxide (NO) bioavailability and elevated carotid artery stiffness, a well-established independent risk factor for end-organ damage and all-cause mortality. In this study, we demonstrate that 12 wk of dietary nitrate supplementation through beetroot extract significantly increased NO bioavailability and improved carotid artery stiffness in postmenopausal females.

Total bilirubin (TBIL) has antioxidant and anti-inflammatory properties. This study aimed to determine whether elevated TBIL could modify the association between diabetes and stroke.

Data were obtained from the National Health and Nutrition Examination Survey 2011-2016. TBIL was stratified by median (10.3 µmol/L). The association between diabetes and stroke was quantified using multivariable logistic regression models. The cut-off concentration for the presence of TBIL modification effects was identified by Johnson-Neyman analyses. Mediation analyses were performed to determine the influence of TBIL on mediating factors that mediate the relationship between diabetes and stroke.

This cross-sectional study included 16 130 participants, with the mean age of 46.8±0.4 years and 48.5% of men. Diabetes was associated with the presence of stroke at TBIL <10.3 µmol/L (OR=2.19, 95% CI 1.58 to 3.05) but not at TBIL ≥10.3 µmol/L (OR=1.27, 95% CI 0.85 to 1.88) after adjustment for confounders. Above associations were significantly different between the two TBIL concentrations (P for interaction=0.03). Moreover, the modification effect of TBIL specifically occurred in men (P for interaction=0.02) rather than in women (P for interaction=0.08). The cut-off concentration for the presence of TBIL modification effects was 17.05 µmol/L. Additionally, the TBIL of ≥10.3 µmol/L inhibited mediating effects of hypersensitive C reactive protein (mediating effect=0.03, 95% CI -0.15 to 0.22, P=0.72) and systemic immune-inflammation index (mediating effect=0.01, 95% CI -0.01 to 0.04, P=0.29) as compared with the TBIL of <10.3 µmol/L.

Elevated TBIL modified the association between diabetes and stroke through inhibiting mediating effects of inflammatory factors.

Right ventricular (RV) adaptation to the increased afterload in the setting of pulmonary hypertension (PH) and other cardiac and pulmonary vascular conditions is a major determinant of survival. Although the RV remains understudied and less well understood than the left ventricle, recent advances have been made in understanding the function and biology of the RV in health and in disease, particularly in PH. RV adaptation in PH exhibits significant sexual dimorphisms in pathophysiology, adaptation, and outcomes. Despite a higher incidence of PH, women consistently demonstrate better RV adaptation and survival rates in the setting of increased RV afterload compared with men. Sexual dimorphisms extend to therapy responsiveness, with women benefiting more from certain pulmonary vasodilators and exhibiting superior RV recovery. In this review we discuss the current literature on sexual dimorphisms in RV structure, function, and molecular pathways in health and disease, as well as in RV-specific clinical manifestations, treatments, and outcomes in PH. Sex steroid-mediated effects as well as emerging studies on sex steroid-independent effects are reviewed. In general, sex steroids such as 17β-estradiol and dehydroepiandrosterone exert RV-protective effects. In contrast, testosterone negatively impacts RV structure and function. Emerging evidence highlights the influence of nonhormonal genetic determinants, such as BMPR1A and DMRT2 loci, which are associated with better RV function in women. A better understanding of the interplay between sex hormones, genetic factors, and RV biology is crucial for advancing and developing RV-directed therapies for patients of either sex.

Previous studies have indicated that patients with uterine fibroids (UF) may have an elevated risk of cardiovascular disease (CVD), although the causal relationship between UF and CVD remains unclear. In this Mendelian randomization (MR) study, we aimed to investigate the causal association between genetic susceptibility to UF and the risk of developing CVD. We extracted summary statistics for single nucleotide polymorphisms associated with UF and 5 CVDs from multiple databases for further analysis. First, we used linkage disequilibrium score regression to assess the genetic correlation across the genome. Next, we performed univariate MR (UVMR), and to ensure the robustness of our results, we conducted sensitivity analyses using several methods. Additionally, we applied multivariable MR (MVMR) to adjust for potential confounders. The linkage disequilibrium score regression results showed that there was no genetic correlation between UF and coronary heart disease, myocardial infarction (MI), atrial fibrillation, heart failure, cardioembolic stroke (CES). The UVMR revealed a significant association between UF and CES (OR = 1.113, 95% confidence interval [CI]: 1.018-1.218, P = .019, PFDR = .047) and a suggestive causal relationship between UF and MI (OR = 0.943, 95% CI: 0.899-0.989, P = .015, PFDR = .075). In the MVMR analysis, after adjusting for a range of potential confounders, the causal relationships between UF and both CES (OR = 1.104, 95% CI = 1.012-1.205, P = .027) and MI (OR = 0.935, 95% CI = 0.882-0.992, P = .025) remained significant. Our study found that UF increase the risk of CES but decrease the risk of MI, providing a theoretical basis for further research into the underlying mechanisms.

Salt sensitivity of blood pressure (SSBP) is an independent risk factor for cardiovascular disease in individuals with or without hypertension. However, the mechanisms and management of SSBP remain unclear, mainly because the diagnosis of this condition relies on salt loading-depletion protocols that are not feasible in the clinic. The prevalence of hypertension is lower in premenopausal women than in men, but this sex-specific difference is reversed after menopause. Whether excessive SSBP in women at any age contributes to this reversal is unknown, but many clinical studies that have rigorously assessed for SSBP using salt loading-depletion protocols have confirmed that SSBP is more prevalent in women than in men, including during premenopausal age. In this Review, we discuss sex-specific mechanisms of SSBP. We describe sex-related differences in renal transporters, hypertensive pregnancy, SSBP in autoimmune disorders and mitogen-activated protein kinase signalling pathways, and highlight limitations and lessons learned from Dahl salt-sensitive rat models.

Coronavirus disease 2019 (COVID-19) is a multi-system disease that can lead to various severe complications. Acute limb ischemia (ALI) has been increasingly recognized as a COVID-19-associated complication that often predicts a poor prognosis. However, the pathophysiology and molecular mechanisms underlying COVID-19-associated ALI remain poorly understood. Hypercoagulability and thrombosis are considered important mechanisms, but we also emphasize the roles of vasospasm, hypoxia, and acidosis in the pathogenesis of the disease. The angiotensin-converting enzyme 2 (ACE2) pathway, inflammation, and platelet activation may be important molecular mechanisms underlying these pathological changes induced by COVID-19. Furthermore, we discuss the hypotheses of risk factors for COVID-19-associated ALI from genetic, age, and gender perspectives based on our analysis of molecular mechanisms. Additionally, we summarize therapeutic approaches such as use of the interleukin-6 (IL-6) blocker tocilizumab, calcium channel blockers, and angiotensin-converting enzyme inhibitors, providing insights for the future treatment of coronavirus-associated limb ischemic diseases.

The prevalence of severe calcific mitral stenosis (MS) is higher in female patients. The aim of the study was to assess the sex-related differences in clinical characteristics and prognosis in patients with severe calcific MS.

Among 7154 adult patients with MS due to mitral annular calcification who underwent echocardiography between October 2010 and August 2020, 287 patients with severe MS were retrospectively analyzed. The endpoint was all-cause mortality. We calculated a propensity score matched analysis with 22 potential confounding covariates including clinical characteristics and medication usage.

In the entire cohort, there was a predominance of female patients (66 %), and the mean age was 72 ± 11 years. While 97 patients (34 %) underwent MV intervention, 190 patients (66 %) were conservatively managed. During a median follow-up of 12 months (25th -75th percentile: 3-29 months), 102 patients (36 %) died. The cumulative survival rate of female patients was lower compared with male patients in conservative treatment group (p = 0.012), while the cumulative survival rate was comparable between the sexes in MV intervention group (p = 0.63). Even after propensity score matching in 170 patients (85 females and 85 males), similar results were obtained (p = 0.012 for conservative treatment group, p = 0.61 for MV intervention group).

Female sex predominated in patients with severe calcific MS. Female patients with severe calcific MS had worse prognosis than male patients when treated conservatively, while in patients undergoing MV intervention, prognosis was similar between the sexes.

Age-related diseases have emerged as a global concern as the population ages. Consequently, understanding the underlying causes of aging and exploring potential anti-aging interventions is imperative. In females, the ovaries serve as the principal organs responsible for ovulation and the production of female hormones. The aging ovaries are related to infertility, menopause, and associated menopausal syndromes, with menopause representing the culmination of ovarian aging. Current evidence indicates that ovarian aging may contribute to dysfunction across multiple organ systems, including, but not limited to, cognitive impairment, osteoporosis, and cardiovascular disease. Nevertheless, due to the widespread distribution of sex hormone receptors throughout the body, ovarian aging affects not only these specific organs but also influences a broader spectrum of age-related diseases in women. Despite this, the impact of ovarian aging on overall age-related diseases has been largely neglected. This review provides a thorough summary of the impact of ovarian aging on age-related diseases, encompassing the nervous, circulatory, locomotor, urinary, digestive, respiratory, and endocrine systems. Additionally, we have outlined prospective therapeutic approaches for addressing both ovarian aging and age-related diseases, with the aim of mitigating their impacts and preserving women's fertility, physical health, and psychological well-being.

To investigate the association between endogenous sex hormone levels and history of tooth loss related to periodontitis in healthy middle-aged to older men and post-menopausal women.

This cross-sectional study included 5649 participants aged 45-84 (mean age, 63 ± 10 years) from the Multi-Ethnic Study of Atherosclerosis cohort who had sex hormone levels measured and answered a questionnaire regarding perceived periodontal status at exam 1. Multivariable logistic regression was used to examine the association of sex hormones (exposure) with history of tooth loss (outcome), stratified by sex.

Among post-menopausal women, higher free testosterone (per 1SD) was associated with a greater prevalence of tooth loss [OR 1.49 (95% CI, 1.08-2.05)], whereas higher sex hormone binding globulin (SHBG) was associated with a lower prevalence of tooth loss [OR 0.74 (0.58-0.94)], after adjustment for cardiometabolic risk factors and reproductive factors. In men, higher free testosterone and lower SHBG were associated with a lower prevalent probability of tooth loss in unadjusted analysis, but these associations lost significance after covariate adjustment.

A higher androgenic sex hormone profile in post-menopausal women (i.e., increased free testosterone, lower SHBG) was associated with an increased prevalence of tooth loss, after adjusting cardiometabolic risk factors. No such association was found in men. These findings suggest that sex hormones may influence or serve as a marker for periodontal health.

This narrative review highlights the impact of exercise on vascular health in females over the lifespan with an emphasis on puberty, pregnancy and menopause. These events encompass substantial changes in sex hormone levels, particularly oestrogens and progesterone. They are also accompanied by distinct adaptations of the central, peripheral and cerebral vasculature. Regular exercise is an effective mechanism to reduce vascular risk in females of all ages, especially for those at higher risk for vascular disorders. However, there are large variabilities in the vascular adaptations to exercise in females that may be related to circulating sex hormone levels. In addition, exogenous hormones, such as oral contraceptives taken after puberty or hormonal replacement therapy taken to mitigate symptoms of menopause, may interact with exercise-induced changes in vascular function. We highlight how more research is needed to understand the optimal exercise interventions to promote vascular health in females across the lifespan, especially during times of hormonal transition.

Estrogen plays a protective role in vascular health due, in part, to its regulation of endothelial inflammation. However, the mechanism(s) by which estrogen negatively regulates inflammatory signaling pathways is not completely understood. MicroRNAs (miRNAs) are recognized as sensitive and selective regulators of cardiovascular function, inflammation, and disease, yet the effects of 17β-estradiol on the endothelial miRNA profile are largely unknown.

The aim of this study was to determine the effect of 17β-estradiol on the expression of inflammation-associated miRNAs in endothelial cells in vitro.

Human Umbilical Vein Endothelial cells (HUVECs) were treated with media in the absence (control) and presence of 17β-estradiol (100 nM) for 24 hr. Thereafter, endothelial cell release of cytokines (IL-6 and IL-8), the intracellular expression of the central protein inflammatory mediator NF-κB, and the levels of inflammatory-associated miRNAs: miR-126, miR-146a, miR-181b, miR-204, and miR-Let-7a, were determined.

17β-estradiol-treated cells released significantly lower levels of IL-6 (47.6±1.5 pg/mL vs. 59.3±4.9 pg/mL) and IL-8 (36.3±2.3 pg/mL vs. 44.0±2.0 pg/mL). Cellular expression of total NF-κB (26.0±2.8 AU vs. 21.2±3.1 AU) was not different between groups; however, activated NF-κB (Ser536) (12.9±1.7 AU vs. 20.2±2.2 AU) was markedly reduced in 17β-estradiol-treated cells as compared to untreated cells. Furthermore, cellular expressions of miR-126 (1.8±0.3 fold), miR-146a (1.7±0.3 fold), miR-181b (2.1±0.4 fold), miR-204 (1.9±0.4 fold), and miR-Let-7a (1.8±0.3 fold) were markedly increased in response to 17β-estradiol treatment.

These data suggest that the anti-inflammatory effect of 17β-estradiol in endothelial cells may be mediated by miRNAs.

We investigated the sex-dependent effects of inflammatory responses in visceral adipose tissue (VAT) and perivascular adipose tissue (PVAT), as well as hematological status, in relation to cardiovascular disorders associated with prediabetes. Using male and female hereditary hypertriglyceridemic (HHTg) rats-a nonobese prediabetic model featuring dyslipidemia, hepatic steatosis, and insulin resistance-we found that HHTg females exhibited more pronounced hypertriglyceridemia than males, while HHTg males had higher non-fasting glucose levels. Additionally, HHTg females had higher platelet counts, larger platelet volumes, and lower antithrombin inhibitory activity. Regarding low-grade chronic inflammation, HHTg males exhibited increased serum leptin and leukocyte levels, while females had increased serum interleukin-6 (IL-6). Both sexes had increased circulating plasminogen activator inhibitor-1 (PAI-1), higher PAI-1 gene expression in VAT and PVAT, and elevated intercellular adhesion molecule-1 (ICAM-1) gene expression in the aorta, contributing to endothelial dysfunction in the HHTg strain. However, HHTg females had lower tumor necrosis factor alpha (TNFα) gene expression in the aorta. Severe dyslipidemia in this prediabetic model was associated with hypercoagulation and low-grade chronic inflammation. The increase in PAI-1 expression in both VAT and PVAT seems to indicate a link between inflammation and vascular dysfunction. Despite the more pronounced dyslipidemia and procoagulation status in females, their milder inflammatory response may reflect an association between reduced cardiovascular damage and prediabetes.

We aim to investigate whether chemical inhibition of NRF2 transcriptional activity (TA) influences distal colon contractions, particularly in an age-dependent manner in females, and whether it impacts oestrogen receptor signalling in female mice. This study was performed on 3 and 6-month-old female mice treated with ML385 (30 mg/kg) or a vehicle for 7 days (i.p.). The colon functionality was verified with a colon bead expulsion test; serum samples were collected for oestradiol levels, and colon samples were stored for various histological analyses. The results show that the seven-day treatment of ML385 significantly downregulated TA (p < 0.05) and impacted its contractility. Additionally, young females treated with ML385 exhibited an increase in goblet cell number and significantly increased ERα, but not ERβ, especially in older mice. It is worth noting that the basal level of the membrane oestrogen receptor GPR30 was higher in older mice within the epithelial layer, and ML385 treatment led to a downregulation of GPR30 in 6-month-old mice. In summary, ML385 decreases NRF2 TA in the colon and impacts its contractility and goblet cell numbers. Additionally, NRF2 TA influences the expression of oestrogen receptors in the colons of female mice.

Foam cell formation is a hallmark of atherosclerosis, yet the cellular complexity within foam cells in human plaques remains unexplored. Here, we integrate published single-cell RNA-sequencing, spatial transcriptomic, and chromatin accessibility sequencing datasets of human atherosclerotic lesions across eight distinct studies. Through this large-scale integration of patient-derived information, we identified foamy macrophages enriched for genes characteristic of the foamy signature. We further re-clustered the foamy macrophages into five unique subsets with distinct potential functions: (i) pro-foamy macrophages, exhibiting relatively high inflammatory and adhesive properties; (ii) phagocytic foamy macrophages, specialized in efferocytosis; (iii) high-efflux foamy macrophages marked by high NR1H3 expression; (iv) mature foamy macrophages prone to programmed cell death; and (v) synthetic subset. Trajectory analysis elucidated a bifurcated differentiation cell fate from pro-foam macrophages toward either the programmed death (iv) or synthetic (v) phenotype. The existence of these foamy macrophage subsets was validated by immunostaining. Moreover, these foamy macrophage subsets exhibited strong potential ligand-receptor interactions. Finally, we conducted Mendelian randomization analyses to identify a possible causal relationship between key regulatory genes along the programmed death pathway in foamy macrophages and atherosclerotic diseases. This study provides a high-resolution map of foam cell diversity and a set of potential key regulatory genes in atherosclerotic plaques, offering novel insights into the multifaceted pathophysiology underlying human atherosclerosis.

The purpose of this study is to investigate the association between Chinese Visceral Adipose Index(CVAI) and brachial-ankle pulse wave velocity (baPWV) in type 2 diabetes (T2D) patients, in order to provide scientific evidence for the prevention and treatment of macrovascular complications in T2D.

This research adopts the cross-sectional study design. Anthropometric assessment, baPWV assessment and biochemical assessment were performed in 2906 T2D patients. CVAI was calculated from the combination of triglycerides, age, high-density lipoprotein cholesterol, waist circumference, body mass index. Multivariate regression analysis and generalized additive model were used to analyze the association between bapwv and CVAI. Subgroup analysis and interaction analysis were used to analyze the influencing factors.

After adjustment for covariates, baPWV tended to increase in the quartiles of CVAI. In males, As CVAI increases by a unit, baPWV was increased by 0.28 cm/s (95% CI: -0.05, 0.61 P=0.0934). In females, As CVAI increases by a unit, baPWV was increased by 1.60 cm/s (95% CI: 1.07, 2.14). A non-linear connection in males and a linear connection in females between the CVAI and baPWV was revealed. In males, we found that CVAI interacted with baPWV in different duration of diabetes (P interaction = 0.0052), alcohol consumption status (P interaction = 0.0375). In females, CVAI interacted with baPWV in glycated hemoglobin (P interaction = 0.0003), systolic blood pressure (P interaction = 0.0001), diastolic blood pressure (P interaction<0.0001), duration of diabetes (P interaction = 0.0014), the use or non-use of glucose-lowering drugs (P interaction = 0.0006), the use or non-use antihypertensive drugs (P interaction = 0.0004), females' menopausal status (P interaction = 0.0012).

The relationship between CVAI and baPWV in T2D patients is positively non-linear in males and linear in females. In all subjects, this relationship was influenced by diabetes duration. In males, drinking status affected this relationship, and in females, It is influenced by blood pressure, glycemic control, menopausal status, and the use of glucose-lowering and hypotensive drug, highlighting the complex interplay between visceral fat and arterial stiffness in the T2D population.

Arterial stiffness (arteriosclerosis) has been linked to heightened risks for cognitive decline, and ultimately for Alzheimer's disease and other forms of dementia. Importantly, neurovascular outcomes generally vary according to one's biological sex. Here, capitalizing on a large sample of participants with neuroimaging and behavioral data (N = 203, age range = 18-87 years), we aimed to provide support for a hierarchical model of neurocognitive aging, which links age-related declines in cerebrovascular health to the rate of cognitive decline via a series of intervening variables, such as white matter integrity. By applying a novel piecewise regression approach to our cross-sectional sample to support Granger-like temporal inferences, we show that, on average, a precipitous decline in cerebral arterial elasticity (measured with diffuse optical imaging of the cerebral arterial pulse; pulse-DOT) precedes an acceleration in the development of white matter lesions by nearly a decade, with women protected from these deleterious effects until approximately age 50, the average onset of menopause. By employing multiple-mediator path analyses while controlling for sex, we show that age may impair cognition via the sequential indirect effects of arteriosclerosis and white matter atrophy on fluid, but not crystallized, abilities. Importantly, we replicate these results using pulse pressure, an independent index of arterial health, thereby providing converging evidence for the central role of arteriosclerosis as an accelerating factor in normal and pathological aging and identifying robust sex-related differences in the progression of cerebral arteriosclerosis and white matter degradation.

Deep and extensive wounds usually cannot be closed directly by suturing or skin grafting. Flap transplantation is typically used to reconstruct large wounds clinically. The flap survival is based on a stable blood perfusion. It is established that estrogen promotes wound healing and angiogenesis, and regulates the inflammatory response, leading to enhanced flap survival after transplantation. However, estrogen concentrations administered in previous studies were significantly higher than physiological levels, potentially causing systemic side effects. Estrogen-sustained-release silastic capsules can maintain blood serum estrogen closer to physiological levels. This study aimed to investigate whether administering estrogen at a lower concentration, closer to physiological levels, could still enhance flap survival.

This study was performed in a random skin flap model in ovariectomized (OVX) mice. Sustained-release estrogen silastic capsules were implanted into OVX mice to determine the functional role of estrogen in wound healing after flap transplantation. Flap blood perfusion was analysed using a colour laser Doppler scanner. Immunohistochemical staining of CD31, hypoxia-inducible factor 1 alpha (HIF-1α), alpha-smooth muscle actin (α-SMA), cleaved caspase 3 and apoptotic terminal dUTP nick end-labelling stain was used to investigate flap angiogenesis, tissue hypoxia, wound healing and cell death in the flap tissue, respectively.

We observed that administering estrogen at a lower concentration enhanced superficial blood perfusion while reducing the flap's ischemic area and tissue necrosis. HIF-1α expression was significantly decreased in the dermis layer but not in the fascia, whereas cleaved caspase 3 levels decreased in the fascia but remained unchanged in the dermis. Additionally, there was no significant difference in CD31and α-SMA expression between the groups.

In summary, the study showed that an estrogen silastic capsule maintained physiological estrogen levels and improved superficial perfusion, thereby reducing dermal hypoxia, and cell death in a mouse random pattern skin flap model. Although no significant promotion of angiogenesis was observed, the study suggests that appropriate estrogen supplements could enhance flap wound recovery.

Cardiorespiratory fitness (CRF) is a vital indicator of overall health and cardiovascular efficiency. Systemic inflammation significantly impacts CRF, and reducing systemic inflammation may serve as an effective strategy to improve CRF. Diet plays a crucial role in systemic inflammation, but daily dietary intake typically involves multiple elements rather than a single nutrient. The Dietary Inflammatory Index (DII) provides an overall assessment of dietary inflammation on the basis of the anti-inflammatory and pro-inflammatory effects of the nutrients consumed. However, the relationship between DII and CRF is not yet well understood.

To examine the association between the DII and CRF.

This study analyzed 3,087 participants from the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2002. The study subjects were divided into three distinct groups by DII tertile: T1 (n = 1,027), T2 (n = 1,029), and T3 (n = 1,031). The associations between DII levels and CRF were examined via logistic regression analysis and restricted cubic splines (RCSs).

Elevated DII scores were significantly linked to low CRF levels. Compared with those in the lowest tertile, participants in the highest DII tertile exhibited a greater prevalence of low CRF (T1: 10.85%, T2: 16.32%, T3: 19.31%). In the model with full adjustments, elevated scores on the DII were consistently linked with a heightened likelihood of low CRF (OR: 1.17, 95% CI: 1.07-1.28; P < 0.001). Compared with those in the T1 group, participants with higher DIIs had an increased risk of lower CRF (T2: OR: 1.42, 95% CI: 1.01-2.01, P = 0.046; T3: OR: 1.71, 95% CI: 1.22-2.40, P = 0.003). Additionally, a significant interaction (P = 0.045) between sex and the DII for low CRF was observed within the population.

A higher DII score is linked to an elevated risk of low CRF. Moreover, sex can impact CRF, with women being more prone to low CRF.

(1) Background: This study utilized a 24-week intervention incorporating heart rate sensors for real-time monitoring of intervention training, aiming to comprehensively assess the effects of Tai Chi on vascular endothelial function, atherosclerosis progression, and lipid metabolism. The insights gained may inform personalized non-pharmacological interventions to enhance the management of cardiovascular health in this population to provide sustainable benefits and improve quality of life. (2) Methods: Forty postmenopausal middle-aged and elderly women were randomly assigned to an exercise or control group. The exercise group underwent a 24-week Tai Chi (BaFa WuBu) training intervention with real-time heart rate monitoring using Polar sensors. Pre- and post-intervention assessments included body composition, blood pressure, vascularity, and blood parameters measured with the Inbody 720, Vascular Endothelial Function Detector, and Arteriosclerosis. Data were analyzed using SPSS 26.0 and mixed-design ANOVA to assess the effects of time, group, and their interactions on study outcomes. (3) Results: After training through 24 weeks of Tai Chi (BaFa WuBu) intervention, compared with the control group, systolic blood pressure in the exercise group was significantly lower (p < 0.05), and the difference between left and right arm pulse pressure, left and right ankle mean arterial pressure, left and right side baPWV, left and right side ABI, TC, TG, LDL, and blood pressure viscosity were all very significantly lower (p < 0.01), and the diastolic blood pressure was significantly higher (p < 0.05). Compared with baseline values in the exercise group, systolic blood pressure, right and left arm pulse pressure difference, right and left ankle mean arterial pressure, right and left side baPWV, right and left side ABI, TC, TG, LDL, and blood pressure viscosity decreased very significantly (p < 0.01) and diastolic blood pressure and FMD increased very significantly (p < 0.01) in the exercise group after the intervention. (4) Conclusions: In our study, a 24-week Tai Chi (BaFa WuBu) program significantly improved vascular health in middle-aged and older postmenopausal women. This simplified Tai Chi form is gentle and effective, ideal for older adults. Regular practice led to reduced vascular obstruction, improved lipid metabolism, and enhanced vascular endothelial function, crucial for preventing vascular diseases. The real-time heart rate sensors used were pivotal, enabling precise monitoring and adjustment of exercise intensity, thereby enhancing the study's scientific rigor and supporting Tai Chi (BaFa WuBu) as a beneficial therapeutic exercise.

Sex and gender-biological and social constructs-significantly impact the prevalence of protective and risk factors, influencing the burden of Alzheimer's disease (AD; amyloid beta and tau) and other pathologies (e.g., cerebrovascular disease) which ultimately shape cognitive trajectories. Understanding the interplay of these factors is central to understanding resilience and resistance mechanisms explaining maintained cognitive function and reduced pathology accumulation in aging and AD. In this narrative review, the ADDRESS! Special Interest Group (Alzheimer's Association) adopted a multidisciplinary approach to provide the foundations and recommendations for future research into sex- and gender-specific drivers of resilience, including a sex/gender-oriented review of risk factors, genetics, AD and non-AD pathologies, brain structure and function, and animal research. We urge the field to adopt a sex/gender-aware approach to resilience to advance our understanding of the intricate interplay of biological and social determinants and consider sex/gender-specific resilience throughout disease stages. HIGHLIGHTS: Sex differences in resilience to cognitive decline vary by age and cognitive status. Initial evidence supports sex-specific distinctions in brain pathology. Findings suggest sex differences in the impact of pathology on cognition. There is a sex-specific change in resilience in the transition to clinical stages. Gender and sex factors warrant study: modifiable, immune, inflammatory, and vascular.

Oestrogen plays a crucial physiological role in both women and men. It regulates reproductive functions and maintains various non-reproductive tissues through its receptors, such as oestrogen receptor 1/oestrogen receptor α (ESR1/Erα), oestrogen receptor 2/oestrogen receptor β (ESR2/Erβ), and G protein-coupled oestrogen receptor 1 (GPER). This hormone is essential for the proper functioning of women's ovaries and uterus. Oestrogen supports testicular function and spermatogenesis in men and contributes to bone density, cardiovascular health, and metabolic processes in both sexes. Nuclear receptors Er-α and Er-β belong to the group of transcription activators that stimulate cell proliferation. In the environment, compounds similar in structure to the oestrogens compete with endogenous hormones for binding sites to receptors and to disrupt homeostasis. The lack of balance in oestrogen levels can lead to infertility, cancer, immunological disorders, and other conditions. Exogenous endocrine-active compounds, such as bisphenol A (BPA), phthalates, and organic phosphoric acid esters, can disrupt signalling pathways responsible for cell division and apoptosis processes. The metabolism of oestrogen and its structurally similar compounds can produce carcinogenic substances. It can also stimulate the growth of cancer cells by regulating genes crucial for cell proliferation and cell cycle progression, with long-term elevated levels linked to hormone-dependent cancers such as breast cancer. Oestrogens can also affect markers of immunological activation and contribute to the development of autoimmune diseases. Hormone replacement therapy, oral contraception, in vitro fertilisation stimulation, and hormonal stimulation of transgender people can increase the risk of breast cancer. Cortisol, similar in structure to oestrogen, can serve as a biomarker associated with the risk of developing breast cancer. The aim of this review is to analyse the sources of oestrogens and their effects on the endogenous and exogenous process of homeostasis.

There are considerable sex differences regarding the risk of cardiovascular disease (CVD), including arterial hypertension, coronary artery disease (CAD) and stroke, as well as chronic renal disease. Women are largely protected from these conditions prior to menopause, and the risk increases following cessation of endogenous estrogen production or after surgical menopause. Cardiovascular diseases in women generally begin to occur at a later age than in men (on average with a delay of 10 years). Cessation of estrogen production also impacts metabolism, increasing the risk of developing obesity and diabetes. In middle-aged individuals, hypertension develops earlier and faster in women than in men, and smoking increases cardiovascular risk to a greater degree in women than it does in men. It is not only estrogen that affects female cardiovascular health and plays a protective role until menopause: other sex hormones such as progesterone and androgen hormones generate a complex balance that differentiates heart and blood vessel function in women compared to men. Estrogens improve vasodilation of epicardial coronary arteries and the coronary microvasculature by augmenting the release of vasodilating factors such as nitric oxide and prostacyclin, which are mechanisms of coronary vasodilatation that are more pronounced in women compared to men. Estrogens are also powerful inhibitors of inflammation, which in part explains their protective effects on CVD and chronic renal disease. Emerging evidence suggests that sex chromosomes also play a significant role in shaping cardiovascular risk. The cardiovascular protection conferred by endogenous estrogens may be extended by hormone therapy, especially using bioidentical hormones and starting treatment early after menopause.

Interest in sex differences related to coronary artery disease (CAD) has steadily increased, and the risk factors for CAD show distinct sex differences. For women, cardiovascular risk increases significantly after menopause due to a decrease in estrogen levels. In older individuals, increased arterial stiffness results in a higher pulse pressure, leading to a more common occurrence of isolated systolic hypertension; these changes are more noticeable in women. While the incidence of diabetes is similar in both sexes, women with diabetes face a 50% higher relative risk of fatal coronary heart disease compared to men. Smoking significantly increases the risk of ischemic heart disease in women, particularly those who are younger. The decrease in estrogen in women leads to a redistribution of fat, resulting in increased abdominal obesity and, consequently, an elevated cardiovascular risk. Pregnancy and reproductive factors also have a significant impact on CAD risks in women. Additionally, disparities exist in medical practice. Women are less likely to be prescribed cardioprotective drugs, referred for interventional or surgical treatments, or included in clinical research than men. By increasing awareness of these sex differences and addressing the disparities, we can progress toward more personalized treatment strategies, ultimately improving patient outcomes.

Arterial stiffness (arteriosclerosis) has been linked to heightened risks for cognitive decline, and ultimately for Alzheimer's disease and other forms of dementia. Importantly, neurovascular outcomes generally vary according to one's biological sex. Here, capitalizing on a large sample of participants with neuroimaging and behavioral data ( N = 203, age range = 18-87 years), we aimed to provide support for a hierarchical model of neurocognitive aging, which links age-related declines in cerebrovascular health to the rate of cognitive decline via a series of intervening variables, such as white matter integrity. By applying a novel piecewise regression approach to our cross-sectional sample to support Granger-like causality inferences, we show that, on average, a precipitous decline in cerebral arterial elasticity (measured with diffuse optical imaging of the cerebral arterial pulse; pulse-DOT) temporally precedes an acceleration in the development of white matter lesions by nearly a decade, with women protected from these deleterious effects until approximately age 50, the average onset of menopause. By employing multiple-mediator path analyses while controlling for sex, we show that age may impair cognition via the sequential indirect effects of arteriosclerosis and white matter atrophy on fluid, but not crystallized, abilities. Importantly, we replicate these results using pulse pressure, an independent index of arterial health, thereby providing converging evidence for the central role of arteriosclerosis as an accelerating factor in normal and pathological aging and identifying robust sex-related differences in the progression of cerebral arteriosclerosis and white matter degradation.

Prior evidence demonstrates that pulse pressure (PP), a surrogate marker of arterial stiffness, is an independent risk factor for mortality and major adverse cardiovascular (CV) events.

The study aimed to identify the association of PP with death, myocardial infarction, and stroke among participants enrolled in large CV outcome clinical trials and determine if this association was impacted by pre-existing CV disease, or specific CV risk factors.

A total of 65,382 individuals, ages 19 to 98 years, that were enrolled in one of five CV outcome trials were analyzed. Baseline demographics, history, blood pressures, and medications were collected. Univariate and multivariable analyses were conducted to explore temporal patterns, risks, and adjusted survival rates.

Mean baseline PP was 52 ± 12 mmHg. For every 10 mmHg increase in PP, there was an increased risk of death, stroke, or myocardial infarction (hazard ratio (HR) 1.11, 95 % CI 1.08 to 1.14, p < 0.001). Similarly, a PP ≥ 60 mmHg demonstrated an HR of 1.27 (95 % CI 1.19 to 1.36, p < 0.001) compared with PP < 60 mmHg. A similar association existed for all subgroups analyzed except for participants with a history of stroke where increasing PP did not increase risk (HR 1.02, 95 % CI 0.95 to 1.10, p = 0.53). PP was a better predictor of adverse outcomes when compared to both systolic and diastolic blood pressures using the AIC and C-index.

Among participants enrolled in CV outcome trials, baseline PP is associated with increased risk of death, myocardial infarction, and stroke for those with pre-existing CV disease and risk factors with the exception of a prior history of stroke.

Tar is the main toxic of cigarettes, and its effect on atherosclerosis progression and the underlying mechanisms remain largely unknown. Vascular smooth muscle cells (VSMCs) play a key role in atherogenesis and plaque vulnerability. The present study sought to investigate the mechanism of atherosclerosis progression through tar-induced VSMC necroptosis, a recently described form of necrosis.

The effect of tar on atherosclerosis progression and VSMC necroptosis was examined in ApoE-/- mice and cultured VSMCs. The role of necroptosis in tar-induced plaque development was evaluated in RIPK3-deletion mice (ApoE-/-RIPK3-/-). The key proteins of necroptosis in carotid plaques of smokers and non-smokers were also examined. Quantitative proteomics of mice aortas was conducted to further investigate the underlying mechanism. Pharmacological approaches were then applied to modulate the expression of targets to verify the regulatory process of tar-induced necroptosis.

Tar administration led to increased atherosclerotic plaque area and reduced collagen and VSMCs in ApoE-/- mice. The expression of RIPK1、RIPK3、and MLKL in VSMCs of plaques were all increased in tar-exposed mice and smokers. RIPK3 deletion protected against VSMC loss and plaque progression stimulated by tar. In mechanistic studies, quantitative proteomics analysis of ApoE-/- mice aortas suggested that tar triggered endoplasmic reticulum (ER) stress. PERK-eIF2α-CHOP axis was activated in tar-treated VSMCs and atherosclerotic plaque. Inhibition of ER stress using 4PBA significantly reduced plaque progression and VSMC necroptosis. Further study revealed that ER stress resulted in calcium (Ca2+) release into mitochondria and cytoplasm. Elevated Ca2+ levels lead to mitochondrial dysfunction and excessive reactive oxygen species (ROS) production, which consequently promote RIPK3-dependent necroptosis. In addition, Ca2+/calmodulin-dependent protein kinase II (CaMKII) activated by cytosolic Ca2+ overload binds to RIPK3, accounting for necroptosis.

The findings revealed that cigarette tar promoted atherosclerosis progression by inducing RIPK3-dependent VSMC necroptosis and identified novel avenues of ER stress and Ca2+ overload.

Myocardial infarction (MI) commonly known as "heart attack" results from the blockage of blood flow to the heart. Postmenopausal women face an elevated risk of MI due to declining estrogen levels, a hormone pivotal in maintaining cardiovascular health. It promotes vasodilation, reduce inflammation, and improves lipid profiles. While estrogen therapy shows promise in mitigating MI risk for postmenopausal woman, its efficacy in prevention and recovery remains a subject of debate. This review provides a critical assessment of existing evidence on estrogen therapy's cardioprotective effects for postmenopausal women. It delves into estrogen's role in vascular function enhancement, inflammation reduction, and lipid metabolism modulation. Additionally, it addresses the various forms of estrogen therapy, administration methods, dosage considerations, safety implications, and associated risks. The review highlights the existing controversies and knowledge gaps related to estrogen therapy for MI prevention. It underscores the urgency for in-depth research to decipher the nexus between estrogen therapy and MI risk, especially concerning primary prevention and specific postmenopausal subgroups. Future studies should investigate optimal formulations, doses, and administration routes of estrogen therapy as well as assess treatment timing and duration. Comparative studies and long-term follow-up are necessary to inform clinical decision-making and improve patient care. Addressing these research gaps will empower clinicians to make more judicious choices about estrogen therapy for MI prevention and recovery in postmenopausal women, aiming for enhanced patient outcomes.

Characterization of the interleukin (IL)-10 knockout (KO) mouse with chronic gut inflammation, cardiovascular dysfunction, and bone loss suggests a critical role for this cytokine in interorgan communication within the gut, bone, and cardiovascular axis. We sought to understand the role of IL-10 in the cross-talk between these systems. Six-week-old IL-10 KO mice and their wild type (WT) counterparts were maintained on a standard rodent diet for 3 or 6 months. Gene expression of proinflammatory markers and Fgf23, serum 17β-estradiol (E2), and cardiac protein expression were assessed. Ileal Il17a and Tnf mRNA increased while Il6 mRNA increased in the bone and heart by at least 2-fold in IL-10 KO mice. Bone Dmp1 and Phex mRNA were repressed at 6 months in IL-10 KO mice, resulting in increased Fgf23 mRNA (~4-fold) that contributed to increased fibrosis. In the IL-10 KO mice, gut bacterial β-glucuronidase activity and ovarian Cyp19a1 mRNA were lower (p < 0.05), consistent with reduced serum E2 and reduced cardiac pNOS3 (Ser1119 ) in these mice. Treatment of ileal lymphocytes with E2 reduced gut inflammation in WT but not IL-10 KO mice. In conclusion, our data suggest that diminished estrogen and defective bone mineralization increased FGF23 which contributed to cardiac fibrosis in the IL-10 KO mouse.

Rates of cerebrovascular disease increase after menopause, which is often attributed to the absence of hormones. It remains unknown whether the cumulative exposure to hormones across a female person's premenopausal life extends the window of cerebrovascular protection to the postmenopausal period. To investigate this, we examined the relationship between lifetime hormone exposure (LHE) and cerebral small vessel disease in more than 9,000 postmenopausal women in the UK-Biobank.

The cohort consisted of women (aged 40-69 years) who attended one of 22 research centers across the United Kingdom between 2006 and 2010. Women were excluded if they were premenopausal when scanned, had missing reproductive history data, self-reported neurologic disorders, brain cancer, cerebral vascular incidents, head or neurologic injury, and nervous system infection. Endogenous LHE (LHEEndo) was estimated by summing the number of years pregnant (LHEParity) with the duration of the reproductive period (LHECycle = age menopause - age menarche). Exogenous LHE (LHEExo) was estimated by summing the number of years on oral contraceptives and hormone replacement therapy. Cerebral small vessel disease was determined by estimating white matter hyperintensity volume (WMHV) from T2-fluid-attenuated inversion recovery brain MRI (acquired between 2014 and 2021), normalized to intracranial volume and log-transformed. Multiple linear regressions were used to assess the relationship between LHEEndo on WMHV adjusted for age, cardiovascular risk factors, sociodemographics, and LHEExo.

A total of 9,163 postmenopausal women (age 64.21 ± 6.81 years) were retained for analysis. Average LHEEndo was 39.77 ± 3.59 years. Women with higher LHEEndo showed smaller WMHV (adj-R 2 = 0.307, LHEEndo β = -0.007 [-0.012 to -0.002], p < 0.01). LHEParity and LHECycle were independent contributors to WMHV (adj-R 2 = 0.308, p << 0.001; LHEParity β = -0.022 [-0.042 to -0.002], p < 0.05; LHECycle β = -0.006 [-0.011 to -0.001], p < 0.05). LHEExo was not significantly related to WMHV (LHEExo β = 0.001 [-0.001 to 0.002], p > 0.05).

Women with more prolonged exposure to endogenous hormones show relatively smaller burden of cerebral small vessel disease independent of the history of oral contraceptive use or hormone replacement therapy. Our results highlight the critical role endogenous hormones play in female brain health and provide real-world evidence of the protective effects premenopausal endogenous hormone exposure plays on postmenopausal cerebrovascular health.

Dr Erik von Willebrand first described a family with bleeding symptoms in a Finnish publication in 1926. A closer look at this landmark publication sheds light on some pathophysiological aspects of von Willebrand disease that may be applicable even in the current era. We attempt to relay in this article how the teachings from this original description may provide a benchmark for further research in this condition.

Pulmonary arterial hypertension (PAH) is a rare cardiovascular disorder leading to pulmonary hypertension and, often fatal, right heart failure. Sex differences in PAH are evident, which primarily presents with a female predominance and increased male severity. Disturbed signalling of the transforming growth factor-β (TGFβ) family and gene mutations in the bone morphogenetic protein receptor 2 (BMPR2) are risk factors for PAH development, but how sex-specific cues affect the TGFβ family signalling in PAH remains poorly understood. In this review, we aim to explore the sex bias in PAH by examining sex differences in the TGFβ signalling family through mechanistical and translational evidence. Sex hormones including oestrogens, progestogens, and androgens, can determine the expression of receptors (including BMPR2), ligands, and soluble antagonists within the TGFβ family in a tissue-specific manner. Furthermore, sex-related genetic processes, i.e. Y-chromosome expression and X-chromosome inactivation, can influence the TGFβ signalling family at multiple levels. Given the clinical and mechanistical similarities, we expect that the conclusions arising from this review may apply also to hereditary haemorrhagic telangiectasia (HHT), a rare vascular disorder affecting the TGFβ signalling family pathway. In summary, we anticipate that investigating the TGFβ signalling family in a sex-specific manner will contribute to further understand the underlying processes leading to PAH and likely HHT.

Dilatation of the thoracic or abdominal aorta can progress to dissection or rupture with significant associated morbidity and mortality. Aortic disease remains a treatable contributor to mortality in the US and its burden is likely underestimated. Recent clinical studies have uncovered sex and gender distinctions in the epidemiology, pathophysiology, and outcomes of aortic disease. Despite this, there has been little progress in the application of these findings to clinical practice. Improved understanding of the sex-specific mechanisms of aortic disease may inform personalized indications for elective repair and thus reduce the morbidity of aortic catastrophe. The objective of this review is to summarize known clinical and biological sex differences in both thoracic and abdominal aortic disease and highlight promising areas for future investigation.

Marfan syndrome causes a hereditary form of thoracic aortic aneurysms with worse outcomes in male compared to female patients. In this study, we examine the effects of 17 β-estradiol on aortic dilation and rupture in a Marfan mouse model. Marfan male mice were administered 17 β-estradiol, and the growth in the aortic root, along with the risk of aortic rupture, was measured. Transcriptomic profiling was used to identify enriched pathways from 17 β-estradiol treatments. Aortic smooth muscle cells were then treated with cytokines to validate functional mechanisms. We show that 17 β-estradiol decreased the size and rate of aortic root dilation and improved survival from rupture. The Marfan transcriptome was enriched in inflammatory genes, and the addition of 17 β-estradiol modulated a set of genes that function through TNFα mediated NF-κB signaling. In addition, 17 β-estradiol suppressed the induction of these TNFα induced genes in aortic smooth muscle cells in vitro in an NF-κB dependent manner, and 17 β-estradiol decreased the formation of adventitial inflammatory foci in aortic roots in vivo. In conclusion, 17 β-estradiol protects against the dilation and rupture of aortic roots in Marfan male mice through the inhibition of TNFα-NF-κB signaling.