No Sex Differences in Inflammatory Response and Vascular Function During Low Estrogen Phase

Aging is a primary risk factor for cardiovascular disease (CVD), which is the leading cause of death in developed countries. Globally, the population of adults over the age of 60 is expected to double by the year 2050. CVD prevalence and mortality rates differ between men and women as they age in part due to sex-specific mechanisms impacting the biological processes of aging. Measures of vascular function offer key insights into cardiovascular health. Changes in vascular function precede changes in CVD prevalence rates in men and women and with aging. A key mechanism underlying these changes in vascular function is the endothelin (ET) system. Studies have demonstrated sex and sex hormone effects on endothelin-1 (ET-1), and its receptors ETA and ETB. However, with aging there is a dysregulation of this system resulting in an imbalance between vasodilation and vasoconstriction. Thus, ET-1 may play a role in the sex differences observed with vascular aging. While most research has been conducted in pre-clinical animal models, we describe more recent translational data in humans showing that the ET system is an important regulator of vascular dysfunction with aging and acts through sex-specific ET receptor mechanisms. In this review, we present translational evidence (cell, tissue, animal, and human) that the ET system is a key mechanism regulating sex-specific changes in vascular function with aging, along with therapeutic interventions to reduce ET-mediated vascular dysfunction associated with aging. More knowledge on the factors responsible for the sex differences with vascular aging allow for optimized therapeutic strategies to attenuate CVD risk in the expanding aging population.

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Abstract 497: Sex Differences in the Relationship Between Pro-Inflammatory Adipokines, Chemerin and Resistin, and Carotid Atherosclerotic Plaque Instability

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.37.suppl_1.497 ◽

2017 ◽

Vol 37 (suppl_1) ◽

Author(s):

Karina Gasbarrino ◽

Russell Yanofsky ◽

Carina Sancho ◽

Fanny Jaunet ◽

Huaien Zheng ◽

...

Keyword(s):

Sex Differences ◽

Mrna Expression ◽

Vascular Function ◽

Carotid Plaque ◽

Fibrous Tissue ◽

Staining Intensity ◽

Plaque Morphology ◽

Plaque Instability ◽

Unstable Plaques ◽

The Relationship

Introduction: Sex differences in plaque morphology and composition exist; men develop more unstable plaques than women. Yet, stroke kills more women than men. Despite these differences, no sex-specific guidelines for carotid disease management exist. Thus, markers that reflect sex-specific morphological features in the plaque should be explored for better prediction of stroke risk. Pro-inflammatory adipokines, chemerin and resistin, influence vascular function. Herein we are the first to investigate sex differences in the relationship between carotid plaque instability and the expression of these adipokines. Methods: Subjects with ≥50% carotid stenosis scheduled for a carotid endarterectomy were recruited from McGill-affiliated hospitals. Pre-operative plasma chemerin and resistin levels were measured using ELISA. Stability of carotid plaque specimens was assessed by two gold standard histological classifications. Stable and unstable plaques were immunostained for chemerin, chemerin’s receptor (ChemR23), and resistin. Digital and semi-quantifications assessed the % area of expression as well as staining intensity (mild to high) and % of positively stained macrophages/foam cells. Plaque mRNA expression was assessed by quantitative PCR. Sex-hormone analyses are ongoing. Results: Men (n=171) had more unstable plaque features, i.e., greater hemorrhage (P=0.022), lipid core size (P<0.001), inflammation (P=0.007), cap infiltration (P=0.006), and less fibrous tissue (P<0.001) than women (n=79). Circulating chemerin and resistin levels were similar between men and women and no sex differences were observed in relation to plaque instability. The % area of chemerin and resistin staining in the plaque was greater in unstable vs stable plaques in men only (P=0.040; P=0.005, respectively). Similarly, greater intensity in chemerin, ChemR23, and resistin staining was associated with plaque instability in men only (P<0.001; P=0.013; P=0.033, respectively). In contrast, lower resistin plaque mRNA expression was associated with plaque instability in women only (P=0.040). Conclusion: Our results suggest the possibility of a sex-dependent regulatory mechanism underlying the connection between these adipokines and plaque instability.

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Sex Differences in the Relation Between Frailty and Endothelial Dysfunction in Old Mice

The Journals of Gerontology Series A ◽

10.1093/gerona/glab317 ◽

2021 ◽

Author(s):

Jazmin A Cole ◽

Mackenzie N Kehmeier ◽

Bradley R Bedell ◽

Sahana Krishna Kumaran ◽

Grant D Henson ◽

...

Keyword(s):

Sex Differences ◽

Endothelial Function ◽

Vascular Function ◽

Mesenteric Artery ◽

Frailty Index ◽

Mesenteric Arteries ◽

Male Mice ◽

Male And Female ◽

Female Mice ◽

Age Related

Abstract Vascular endothelial function declines with age on average, but there is high variability in the magnitude of this decline within populations. Measurements of frailty, known as frailty index (FI), can be used as surrogates for biological age, but it is unknown if frailty relates to the age-related decline in vascular function. To examine this relation, we studied young (4-9 months) and old (23-32 months) C57BL6 mice of both sexes. We found that FI was greater in old compared with young mice, but did not differ between old male and female mice. Middle cerebral artery (MCA) and mesenteric artery endothelium-dependent dilation (EDD) also did not differ between old male and female mice; however, there were sex differences in the relations between FI and EDD. For the MCA, FI was inversely related to EDD among old female mice, but not old male mice. In contrast, for the mesenteric artery, FI was inversely related to EDD among old male mice, but not old female mice. A higher FI was related to a greater improvement in EDD with the superoxide scavenger TEMPOL in the MCAs for old female mice and in the mesenteric arteries for old male mice. FI related to mesenteric artery gene expression negatively for extracellular superoxide dismutase (Sod3) and positively for interleukin-1β (Il1b). In summary, we found that the relation between frailty and endothelial function is dependent on sex and the artery examined. Arterial oxidative stress and pro-inflammatory signaling are potential mediators of the relations of frailty and endothelial function.

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Abstract P537: Reduced Cardiovascular Regenerative Capacity is Associated With Enhanced Inflammatory Response to Acute Psychological Stress

Circulation ◽

10.1161/circ.141.suppl_1.p537 ◽

2020 ◽

Vol 141 (Suppl_1) ◽

Author(s):

Zakaria Almuwaqqat ◽

Jeong Hwan Kim ◽

Muhammad Hammadah ◽

Shabatun Islam ◽

Bruno B Lima ◽

...

Keyword(s):

Inflammatory Response ◽

Vascular Function ◽

Mental Stress ◽

Mononuclear Cells ◽

Patient Characteristics ◽

Adverse Outcomes ◽

Regenerative Capacity ◽

Vascular Regeneration ◽

Before And After ◽

Artery Disease

Background: Bone marrow-derived progenitor cells (PCs) are involved in vascular regeneration and correlate with vascular function and cumulative cardiovascular risk. Systemic inflammation is associated with increased mobilization and differentiation of circulating PCs (CPCs) which may ultimately lead to exhaustion of vascular regenerative capacity. Individuals with coronary artery disease (CAD) exhibit a pro-inflammatory response to a mental stress challenge that has been associated with an elevated risk of adverse outcomes. We sought to determine whether subjects with reduced numbers of circulating PCs (CPCs) are at higher risk of a pro-inflammatory response to acute mental stress. Methods: 500 outpatients with stable CAD were enrolled into the Mental Stress Ischemia Prognosis study and underwent a laboratory-based mental stress protocol. Mononuclear cells expressing CD45med, CD34 and CXCR4 epitopes, known to be enriched for hematopoietic PCs, were enumerated using flow cytometry. Interleukin-6 (IL6) and C-Reactive Protein (CRP) levels were measured before and after mental stress. Baseline and changes in IL6 levels were compared across CPC tertiles using linear regression after adjusting for patient characteristics. Results: Mean age was 63± 9 years, 77% male, 70% white. Median CD34+ CPC count was 1.64 (1.02-2.43 cells/μL. CPC levels were not associated with either the baseline IL6 level (Beta= 0.071 95%CI, -0.091, 0.23) or CRP levels (Beta, 0.60, 95%CI, -0.25, 0.44). However, independent of demographics, CAD risk factors and baseline IL6 levels, lower CD34+/CXCR4+ CPC counts were associated with a higher inflammatory response during mental stress, measured as a rise in IL6 level (Beta= -0.11, 95%CI, -0.20, -0.028). Conclusions: Patients with reduced CPC levels have a greater pro-inflammatory response to mental stress. Thus, the observed higher risk in subjects with impaired regenerative capacity might be at least partly due to a higher stress-related pro-inflammatory response.

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Sex differences in noninvasive vascular function in the community

Journal of Hypertension ◽

10.1097/hjh.0b013e328360f755 ◽

2013 ◽

Vol 31 (7) ◽

pp. 1437-1446 ◽

Cited By ~ 10

Author(s):

Renate B. Schnabel ◽

Moritz P. Biener ◽

Sandra Wilde ◽

Christoph R. Sinning ◽

Francisco M. Ojeda ◽

...

Keyword(s):

Sex Differences ◽

Vascular Function

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Intrinsic sex-specific differences in microvascular endothelial cell phosphodiesterases

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00252.2009 ◽

2010 ◽

Vol 298 (4) ◽

pp. H1146-H1154 ◽

Cited By ~ 42

Author(s):

Jianjie Wang ◽

Susan Bingaman ◽

Virginia H. Huxley

Keyword(s):

Sex Differences ◽

Barrier Function ◽

Vascular Function ◽

Gonadal Hormones ◽

Female Rats ◽

Gonadal Hormone ◽

Microvascular Endothelial Cell ◽

Mrna Levels ◽

Male And Female Rats ◽

Microvascular Endothelial

The importance of gonadal hormones in the regulation of vascular function has been documented. An alternate and essential contribution of the sex chromosomes to sex differences in vascular function is poorly understood. We reported previously sex differences in microvessel permeability ( Ps) responses to adenosine that were mediated by the cAMP signaling pathway (Wang J, PhD thesis, 2005; Wang J and Huxley V, Proceedings of the VIII World Congress of Microcirculation, 2007 ; Wang J and Huxley VH, Am J Physiol Heart Circ Physiol 291: H3094–H3105, 2006). The two cyclic nucleotides, cAMP and cGMP, central to the regulation of vascular barrier integrity, are hydrolyzed by phosphodiesterases (PDE). We hypothesized that microvascular endothelial cells (EC) would retain intrinsic and inheritable sexually dimorphic genes with respect to the PDEs modulating EC barrier function. Primary cultured microvascular EC from skeletal muscles isolated from male and female rats, respectively, were used. SRY (a sex-determining region Y gene) mRNA expression was observed exclusively in male, not female, cells. The predominant isoform among PDE1–5, present in both XY and XX EC, was PDE4. Expression mRNA levels of PDE1A (male > female) and PDE3B (male < female) were sex dependent; PDE2A, PDE4D, and PDE5A were sex independent. Barrier function, Ps, was determined from measures of albumin flux across confluent primary cultured microvessel XY and XX EC monolayers. Consistent with intact in situ microvessels, basal monolayer Ps did not differ between XY (1.7 ± 0.2 × 10−6 cm/s; n = 8) and XX (1.8 ± 0.1 × 10−6 cm/s; n = 10) EC. Cilostazol, a PDE3 inhibitor, reduced (11%, P < 0.05) Ps in XX, not XY, cells. These findings demonstrate the presence and maintenance of intrinsic sex-related differences in gene expression and cellular phenotype by microvascular EC in a gonadal-hormone-free environment. Furthermore, intrinsic cell-sex likely contributes significantly to sexual dimorphism in cardiovascular function.

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Sex differences in the inflammatory response and inflammation-induced vascular dysfunction

The Lancet ◽

10.1016/s0140-6736(17)30416-6 ◽

2017 ◽

Vol 389 ◽

pp. S20 ◽

Cited By ~ 2

Author(s):

Krishnaraj Rathod ◽

Vikas Kapil ◽

Shanti Velmurugan ◽

Rayomand Khambata ◽

Umme Siddique ◽

...

Keyword(s):

Sex Differences ◽

Inflammatory Response ◽

Vascular Dysfunction

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Sex Differences in Inflammatory Response and Acid–Base Balance in Prepubertal Children with Severe Sepsis

Shock ◽

10.1097/shk.0000000000000773 ◽

2017 ◽

Vol 47 (4) ◽

pp. 422-428 ◽

Cited By ~ 2

Author(s):

Nicolas Lefèvre ◽

Benjamin Noyon ◽

Dominique Biarent ◽

Francis Corazza ◽

Jean Duchateau ◽

...

Keyword(s):

Sex Differences ◽

Severe Sepsis ◽

Inflammatory Response ◽

Acid Base Balance ◽

Acid Base ◽

Prepubertal Children ◽

Base Balance

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Age and sex relationship with flow-mediated dilation in healthy children and adolescents

Journal of Applied Physiology ◽

10.1152/japplphysiol.01113.2014 ◽

2015 ◽

Vol 119 (8) ◽

pp. 926-933 ◽

Cited By ~ 7

Author(s):

Nicola D. Hopkins ◽

Donald R. Dengel ◽

Gareth Stratton ◽

Aaron S. Kelly ◽

Julia Steinberger ◽

...

Keyword(s):

Sex Differences ◽

Children And Adolescents ◽

Brachial Artery ◽

Vascular Function ◽

Growth Patterns ◽

Childhood And Adolescence ◽

Flow Mediated Dilation ◽

Healthy Children ◽

Asymptomatic Children ◽

Age And Sex

Flow-mediated dilation (FMD) is a noninvasive technique used to measure conduit artery vascular function. Limited information is available on normative FMD values in healthy children and adolescents. The objective of this study was to assess relationships between age and sex with FMD across childhood and adolescence. Nine hundred and seventy-eight asymptomatic children (12 ± 3 yr, range 6–18 yr, 530 male) underwent ultrasonic brachial artery assessment before and after 5 min of forearm ischemia. Sex differences in FMD and baseline artery diameter were assessed using mixed linear models. Baseline artery diameter was smaller in females than males [2.96 mm (95% CI: 2.92–3.00) vs. 3.24 mm (3.19–3.28), P < 0.001] and increased with age across the cohort ( P < 0.001). Diameter increased between ages 6 and 17 yr in males [from 2.81 mm (2.63, 3.00) to 3.91 mm (3.68, 4.14)] but plateaued at age 12 yr in females. Males had a lower FMD [7.62% (7.33–7.91) vs. 8.31% (7.95–8.66), P = 0.024], specifically at ages 17 and 18 yr. There was a significant effect of age on FMD ( P = 0.023), with a reduction in FMD apparent postpuberty in males. In conclusion, the brachial artery increases structurally with age in both sexes; however, there are sex differences in the timing and rate of growth, in line with typical sex-specific adolescent growth patterns. Males have a lower FMD than females, and FMD appears to decline with age; however, these findings are driven by reductions in FMD as males near maturity. The use of age- and sex-specific FMD data may therefore not be pertinent in childhood and adolescence.

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Sex differences in vascular function: implication of endothelium-derived hyperpolarizing factor

Journal of Endocrinology ◽

10.1677/joe-08-0070 ◽

2008 ◽

Vol 197 (3) ◽

pp. 447-462 ◽

Cited By ~ 46

Author(s):

Inmaculada C Villar ◽

Adrian J Hobbs ◽

Amrita Ahluwalia

Keyword(s):

Sex Differences ◽

Sex Hormones ◽

Vascular Function ◽

Vascular Tone ◽

Inflammatory Responses ◽

Vascular Inflammation ◽

Critical Role ◽

Premenopausal Women ◽

Circulating Cells ◽

Inflammatory Processes

The vascular endothelium plays a crucial role in the regulation of vascular homeostasis by controlling vascular tone, coagulation, and inflammatory responses. These actions are exerted by endothelial factors including nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor (EDHF). The greater incidence of cardiovascular disease (CVD) in men and postmenopausal women compared with premenopausal women implies a vasoprotective phenotype of females, which may be influenced by sex hormones. These hormones, particularly estrogen, have modulatory effects on the endothelium and circulating cells that have been implicated in vascular inflammation and in the development of CVD. EDHF seems to be the predominant endothelial factor in the resistance vasculature of females and this mediator could afford the beneficial cardiovascular risk profile observed in premenopausal woman. In this review, we discuss sex differences in EDHF biology and how sex hormones can modulate EDHF responses. We also review the implication of sex hormone-dependent regulation of EDHF in inflammatory processes, platelet function, and repair after vascular damage, each of which have a critical role in several aspects of the pathogenesis of CVD.

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