Sex Differences In Vascular Function Research Articles

The influence of physical activity and sex on carotid artery longitudinal wall motion in younger healthy adults.

Carotid artery longitudinal wall motion (CALM) is a novel preclinical marker for atherosclerosis that describes the axial anterograde and retrograde motion of the intima-media complex. While regular physical activity and sex are known to independently influence arterial stiffness, their roles on axial arterial wall behaviour are unknown. The purpose of this study is to examine whether physical activity and sex impact CALM. We hypothesized that CALM retrograde displacement and total amplitude would be greater in females and active individuals, as a function of arterial stiffness. Fifty-seven young healthy adults (30 females; aged 22±3 years) were evaluated for CALM outcomes and arterial stiffness and grouped by physical activity based on active (V̇O2=44.2±8.9mL/kg/min) or sedentary (V̇O2=33.7±6.7mL/kg/min) lifestyles defined by the Canadian 24-Hour Movement Guidelines. Arterial stiffness and CALM were measured by carotid-femoral pulse wave velocity (cfPWV) and vascular ultrasound at the right common carotid artery with speckle tracking analysis, respectively. cfPWV was greater in males (p<0.01) with no interaction between sex and physical activity (p=0.90). CALM anterograde displacement was greater in males (p=0.03) resulting in a forward shift in total CALM pattern, which became less prominent when controlling for mean arterial pressure (p=0.06). All other CALM outcomes were not different between activity and sex. V̇O2max was not correlated to any CALM outcome (all p>0.05). Apparent sex differences in vascular function extend to novel CALM outcomes but may be confounded by blood pressure. We recommend sex-balanced design and reporting in future studies due to possible anterograde-shifted CALM patterns in healthy males.

Sex Differences in Vascular Endothelial Function After Liver Transplant

INTRODUCTIONLiver transplant (LT) recipients have an increased risk of developing cardiovascular disease (CVD) after transplant. Sex differences may be a significant determinant in the pathophysiology of CVD. However, sex‐differences in vascular dysfunction, an established precursor to CVD, have not been explored in LT recipients. The purpose of this study was to investigate the sex differences in vascular function and cardiometabolic risk‐factors to CVD among LT patients.METHODSConduit artery endothelial function was measured via flow‐mediated dilation of the brachial artery (FMDBA) with duplex ultrasound in 23 age‐matched LT patients (11 Male, 12 Female; Mean ± SEM: Age 55 ± 2 years). Aortic pressure waves were synthesized from radial artery waveforms acquired by applanation tonometry and the use of a generalized transfer function. Novel plasma based cardiometabolic risk factors were assessed with nuclear magnetic resonance spectroscopy. Lipoprotein insulin resistance index (LPIR) was calculated as a weighted combination of concentrations and particle sizes of very low‐density, low‐density, and high‐density lipoproteins. Diabetes risk index (DRI) factors LPIR and branched‐chain amino acid levels to predict the risk of type 2 diabetes. Metabolic inflammation index (INFX) combines concentrations of the inflammation biomarker GlycA and high‐density lipoprotein particle subspecies.RESULTSMales had lower FMDBA than females (3.98 ± 0.63 vs 6.27 ± 0.43%, p &lt; 0.01). There were no sex differences in aortic systolic pressure (Male vs Female; 129 ± 3 vs 118 ± 5 mmHg, p = 0.09), body mass index (38 ± 2 vs 36 ± 2 kg/m2, p = 0.61), LPIR (57 ± 7 vs 55 ± 7, p = 0.89), DRI (53 ± 7 vs 44 ± 6, p = 0.38), or INFX (47 ± 2 vs 54 ± 3, p = 0.13).CONCLUSIONSMales had poorer vascular endothelial function compared to females following LT, suggesting that males may be more susceptible to the development of CVD after LT. However, this increased risk cannot be explained by differences in traditional cardiometabolic risk factors. Future research should identify non‐traditional CVD risk factors that contribute to sex differences in vascular function towards implementing precision medicine for the prevention and management of CVD in LT patients.

Abstract 13944: Young, Non-Hispanic Black Males and Females Exhibit Divergent Peripheral and Cerebral Vascular Reactivity

Introduction: In the U.S., cardiovascular and cerebrovascular diseases (CVD) remain more prominent in non-Hispanic black individuals than in other populations. Across most racial/ethnic groups, total CVD prevalence is ~10% lower in females; however, total CVD prevalence in black females (BF) is similar to that of black males (BM). Conversely, BM have ~23% higher age-adjusted stroke mortality compared to BF, a pattern not seen in other groups. While the mechanisms behind these race-by-sex differences are multifactorial, vascular dysfunction likely contributes. Our group and others have demonstrated reduced brachial artery and cerebrovascular vasodilation in black versus white individuals, though much of this work did not specifically address sex differences. To this end, we have recently investigated and reported divergent mechanisms of reduced cutaneous microvascular function in BM and BF; however, more work is needed to better understand whether such findings extend to other vascular regions. Hypothesis: We tested the hypothesis that BF and BM would have divergent degrees of reduced peripheral and cerebral vasodilator responsiveness. Methods: Eleven BF and 15 BM (22 ± 4 vs. 23 ± 3 yrs) underwent testing for brachial artery flow-mediated dilation (FMD; conduit artery function) and post-occlusive reactive hyperemia (PORH; microvascular function), along with cerebrovascular reactivity (CVR) to rebreathing-induced hypercapnia. Results: FMD was greater in BF versus BM (9.10 ± 3.49 vs. 5.84 ± 2.78%; P = 0.02), even when normalized to baseline diameter or shear rate ( P &lt; 0.05 for both). BF had similar PORH when assessed as peak blood velocity (77.1 ± 19.9 vs. 79.4 ± 19.6 cm • s -1 ; P &gt; 0.05) but lower peak blood flow (343.6 ± 169.8 vs. 495.4 ± 196.9 mL/min; P &lt; 0.05) and blood flow AUC (133.6 ± 61.1 vs. 220.3 ± 130.7 mL; P = 0.04) relative to BM. CVR was greater in BF versus BM (0.024 ± 0.010 vs. 0.012 ± 0.006 cm • s -1 • mmHg -1 • mmHg -1 ; P &lt; 0.01). Conclusion: These data suggest that young, BM have lower vascular reactivity than BF during some, but not all, tests of vascular function. More work in this area is needed to better understand the potential biological and social mechanisms influencing sex differences in vascular function and CVD risk in black individuals.

Similar inflammatory response and conduit artery vascular function between sexes following induced inflammation

What is the central question of this study? Are there sex differences in vascular function following induced inflammation when oestrogen is typically similar between sexes? What is the main finding and its importance? The present study suggests no sex differences in conduit artery vascular responses to acutely induced inflammation during the low-oestrogen phase of the menstrual cycle in premenopausal women. However, women exhibit lower microvascular function than men. Overall, the results underpin the role of oestrogen in previously observed sex differences and the importance of reporting the phase in the hormonal cycle when women are studied. Sex differences in cardiovascular disease incidence in premenopausal women and age-matched men have been attributed to the cardioprotective influence of oestrogen. However, limited knowledge exists regarding sex differences following acute inflammation when oestrogen concentrations are lower in women. We evaluated sex differences in vascular responses to induced inflammation when oestrogen concentrations are typically lower in women (early follicular phase or placebo phase of hormonal contraception). In 15 women and 14 men, interleukin-6 (IL-6) concentrations and vascular function [via brachial artery flow-mediated dilatation (FMD)] were assessed at baseline (BL) and 24 (24H) and 48hours (48H) after administration of influenza vaccine. After induction of inflammation, both sexes exhibited an increase in IL-6 concentrations at 24H [mean (SD) BL vs. 24H: women, 0.563 (0.50) vs. 1.141 (0.65) pg/ml; men, 0.385 (0.17) vs. 1.113 (0.69) pg/ml; P<0.05] that returned to near-baseline concentrations by 48H (BL vs. 48H, P>0.05). There were no sex differences in FMD, allometrically scaled FMD or IL-6 concentrations at any time point (P>0.05). Notably, women exhibited significantly lower microvascular function than men at every time point [P<0.05; reactive hyperaemic area under the curve (in arbitrary units): women, BL 35,512 (14,916), 24H 34,428 (14,292) and 48H 39,467 (13,936); men, BL 61,748 (27,324), 24H 75,028 (29,051) and 48H 59,532 (13,960)]. When oestrogen concentrations are typically lower in women, women exhibit a similar inflammatory response and conduit artery function, but lower microvascular response to reactive hyperaemia, in comparison to age-matched men.

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

Premenopausal women experience a lower incidence of cardiovascular disease as compared to age-matched men, partially due to the cardioprotective effects of estrogen. Acute inflammation increases pro-inflammatory cytokine production and reduces nitric oxide bioavailability, resulting in impaired vascular function. Estrogen has both anti-inflammatory and pro-vasodilatory properties. During the high estrogen mid-luteal phase of the menstrual cycle, sex differences in vascular function and inflammatory responses to induced inflammation have been observed in premenopausal women as compared with age-matched men. However, limited knowledge exists regarding sex differences in estrogen independent responses to acute inflammation. Thus, our objective was to evaluate sex differences in vascular responses to induced inflammation- with a reduced influence of estrogen concentration. Due to the dampening of estrogen-related anti-inflammatory and pro-vasodilatory effects when estrogen concentrations are low, we hypothesized that women would experience a greater inflammatory response as compared with men and that women and men would exhibit similar vascular function. In a double-blind crossover sham-controlled study of 15 women (21 ± 3y) and 15 men (21 ± 2y), we assessed pro-inflammatory interleukin-6 concentration ([IL-6]) and vascular function via brachial artery flow-mediated dilation (FMD) at baseline (BL), 24 hours (24H), and 48 hours (48H) after influenza vaccine administration. Women were studied when circulating estrogen levels are typically low (early follicular phase or placebo pill phase of oral contraceptive pills) and similar between sexes. Following induced inflammation, both sexes exhibited an increase in [IL-6] at 24H (BL v 24H: women p=0.0049; men p=0.0015) that returned to near baseline levels by 48H (BL v 48H: women p=0.43; men p=0.29; [IL-6] (pg/mL): women BL: 0.56 ± 0.5, 24H: 1.14 ± 0.7, 48H: 0.59 ± 0.4; men BL: 0.38 ± 0.2, 24H: 1.05 ± 0.7, 48H: 0.56 ± 0.2). There were no sex differences in FMD or [IL-6] at any time point (FMD: sex p=0.062, time p=0.30, interaction p=0.25; FMD (%): women BL: 8.33 ± 4.8, 24H: 6.40 ± 4.4, 48H: 9.05 ± 5.5; men: BL: 5.25 ± 2.9, 24H: 6.14 ± 2.1, 48H: 6.71 ± 1.1; [IL-6]: BL: p=0.38, 24H: p=0.57, 48H: p=0.99). Notably, women exhibited significantly lower resting brachial artery diameter (BL D; p<0.0001 all time points) than men (BL D (mm): women BL: 3.22 ± 0.4, 24H: 3.18 ± 0.4, 48H: 3.19 ± 0.4; men BL: 4.07 ± 0.6, 24H: 4.24 ± 0.4, 48H, 4.22 ± 0.4). Due to sex difference in baseline diameter, we allometrically scaled FMD to normalize the flow-mediated response to variability in baseline diameter between the sexes. However, there were no sex differences in allometrically scaled FMD (sex p=0.11, time p=0.20, interaction p= 0.072; Scaled FMD (%): women BL: 6.39 ± 3.7, 24H: 4.32 ± 3.8, 48H: 6.92 ± 3.7; men BL: 7.03 ± 3.9, 24H: 8.71 ± 4.2, 48H: 8.69 ± 4.3). When estrogen concentrations are low, women show similar inflammatory responses and vascular function as compared with age-matched men, suggesting a primary role of estrogen in previously observed sex differences in inflammatory responses and vascular function.

Point: Investigators should control for menstrual cycle phase when performing studies of vascular control that include women.

Sex hormones impact vascular function, both on molecular and functional levels. Since sex hormones fluctuate across the normal menstrual cycle, it is critical to control for phase of the menstrual cycle when designing research studies. Ignoring the phase of the menstrual cycle when testing women in physiology studies disregards the crucial roles played by estrogens and progesterone in cardiovascular regulation, and scientists can miss the opportunity to determine biological sources of sex differences in vascular function.

Sex differences in endothelial function in chronic kidney disease.

Vascular dysfunction plays an important role in the etiology of chronic kidney disease (CKD) and is associated with cardiovascular diseases. Sex differences in vascular function are common in clinical and nonclinical populations. However, no data exist in individuals with CKD. The present study tested the hypothesis that sex and/or aging differences exist in vascular function in patients with CKD. Endothelium-dependent dilation (EDD; measured via brachial artery flow-mediated dilation) and endothelium-independent dilation (EID; measured via nitroglycerin-mediated dilation) were assessed. Analyses were adjusted for several variables that could influence vascular function (diabetes, cardiovascular disease, and blood pressure). Women, in general, had higher EDD values than men (6.5 ± 4.9% vs. 4.4 ± 3.4%); however, EID did not differ among these groups. In younger men and women (<55 yr old), EDD and EID were higher (P < 0.05) than their older (≥55 yr old) counterparts (EDD: 7.0 ± 4.1% vs. 4.4 ± 3.8% and EID: 24.0 ± 9.6% vs. 18.3 ± 9.2%). Additionally, younger women exhibited higher (P < 0.05) EDD and EID compared with younger men (EDD: 9.5 ± 6.4% vs. 5.1 ± 3.8%, P = 0.01, and EID: 24.0 ± 9.6% vs. 18.3 ± 9.2%). No differences in EDD and EID were present between older men and women with CKD. Diabetes independently predicted lower EID but not EDD in men and women. Blood pressure and cardiovascular disease did not predict EDD or EID. This is the first study to show significant sex differences in vascular function. Moreover, these differences are evident between younger men and women with CKD but are abolished with age. Additional studies are needed to better understand the mechanisms that may underlie sex differences in vascular dysfunction with CKD.

Sex differences in ET‐1 levels in primary human endothelial cells

Endothelin‐1 (ET‐1) is produced and secreted primarily by endothelial cells and acts as a potent vasoconstrictor. Our laboratory has previously shown that ET‐1 contributes to impaired vascular endothelial function in postmenopausal women (PMW). However, compared to PMW, ET‐1 mediated vasoconstriction is greater in men of a similar age. Although sex differences in ET‐1 receptor expression and/or responses may partially explain these differences, it is unknown whether ET‐1 levels in endothelial cells differ between PMW and men of similar age. The purpose of this study was to test the hypothesis that PMW have lower endothelial cell ET‐1 levels compared to men of similar age. Endothelial cells were harvested from the antecubital vein of healthy PMW (n=9, 59±3 yrs) and age‐matched men (n=7, 58±6 yrs) by threading a guide wire through an 18g IV catheter. The guide wire was rinsed in dissociation buffer to remove endothelial cells, which were then fixed in 4% paraformaldehyde, washed in phosphate buffered saline, pipetted onto coverglass, dried at 60°C, and stored at −80°C until staining. Immunocytochemistry was used to stain for ET‐1 (Endothelin‐1 Monoclonal Antibody (TR.ET.48.5), Thermo Fisher Scientific, Cat# MA3‐005), vascular endothelial cadherin (VE‐Cadherin polyclonal antibody, Thermo Fisher Scientific, Cat# 36‐1900) to identify endothelial cells, and 4′,6‐diamidino‐2‐phenylindole (DAPI, nuclear stain). Fluorescence intensity was measured in 30 cells on a Zeiss Axio imager using consistent laser intensity and exposure times. ET‐1 intensity was normalized to human umbilical vein endothelial cells, consistent with published literature. Results are reported as mean ± standard deviation. PMW and men were well match based on BMI (PMW; 25±5 kg/m2 vs. Men; 25±3), mean arterial blood pressure (PMW; 88±8 vs. Men; 93±9 mmHg), total cholesterol (PMW; 193±45 vs. Men; 192±40 mg/dL), LDL cholesterol (PMW; 103±39 vs. Men; 111±34 mg/dL), and fasting plasma glucose (PMW; 88±4 vs. Men; 92±6 mg/dL) all P&gt;0.05. ET‐1 intensity levels were significantly lower in PMW (0.57±0.12 a.u) compared to Men (0.98±0.27 a.u, P =0.001). These preliminary findings suggest differences in endothelial ET‐1 levels between PMW and age‐matched men. Moreover, these data provide further evidence of the sexual dimorphisms in the ET‐1 system, and add insight into mechanisms underlying sex differences in vascular function.Support or Funding InformationNIH R01 HL 146558, HL‐113514, P20 GM 113125, AHA 16SDG30700015, and University of Delaware Research Foundation.

Sex differences in the vascular function and related mechanisms: role of 17β-estradiol.

The incidence of cardiovascular disease (CVD) is lower in premenopausal women but increases with age and menopause compared with similarly aged men. Based on the prevalence of CVD in postmenopausal women, sex hormone-dependent mechanisms have been postulated to be the primary factors responsible for the protection from CVD in premenopausal women. Recent Women's Health Initiative studies, Cochrane Review studies, the Early Versus Late Intervention Trial with Estradiol Study, and the Kronos Early Estrogen Prevention Study have suggested that beneficial effects of hormone replacement therapy (HRT) are seen in women of <60 yr of age and if initiated within <10 yr of menopause. In contrast, the beneficial effects of HRT are not seen in women of >60 yr of age and if commenced after 10 yr of menopause. The higher incidence of CVD and the failure of HRT in postmenopausal aged women could be partly associated with fundamental differences in the vascular structure and function between men and women and in between pre- and postmenopausal women, respectively. In this regard, previous studies from human and animal studies have identified several sex differences in vascular function and associated mechanisms. The female sex hormone 17β-estradiol regulates the majority of these mechanisms. In this review, we summarize the sex differences in vascular structure, myogenic properties, endothelium-dependent and -independent mechanisms, and the role of 17β-estradiol in the regulation of vascular function.

Sex differences in vascular dysfunction and cardiovascular outcomes: The cardiac, endothelial function, and arterial stiffness in ESRD (CERES) study.

Recent studies suggest that women with end-stage renal disease (ESRD) may have higher rates of mortality than men, but it is unknown whether sex differences in vascular function explain this disparity. The cardiac, endothelial function, and arterial stiffness in ESRD (CERES) study is an ongoing, prospective observational study designed to investigate vascular function, myocardial injury, and cardiovascular outcomes in ESRD. Among 200 CERES participants (34% women), we evaluated arterial wave reflections as augmentation index normalized to a heart rate of 75 (AIx75), arterial stiffness as pulse wave velocity, and macro- and microvascular endothelial dysfunction as flow-mediated dilation and velocity time integral (VTI). Over a median of 14 months, participants were followed for the composite outcome of cardiovascular hospitalization or all-cause death. Women had higher arterial wave reflection (Mean, SD AIx75 30% ± 9% for women vs. 21% ± 10% for men; P < 0.001) and worse microvascular function (VTI 55 ± 30 cm for women vs. 70 ± 27 cm for men; P = 0.007). After multivariable adjustment, female sex remained associated with a 0.5-SD higher AIx75 (95% CI [0.01, 0.9]) and 0.3-SD lower VTI (95%CI [0.1, 0.7]). Women experienced higher adjusted rates of the composite outcome (HR 2.5; 95%CI [1.1, 5.6]; P = 0.03), and further adjustment for arterial wave reflection attenuated this risk. Vascular dysfunction may partly explain the association of female sex with higher cardiovascular risk and mortality in patients with ESRD. Further studies are needed to explore whether sex differences in vascular function predict long-term outcomes, and whether hormonal or inflammatory factors explain these associations.

Influence of sex on microvascular and macrovascular responses to prolonged sitting

Increased daily sitting time is associated with greater cardiovascular risk, and, on average, women are more sedentary than men. Recent reports have demonstrated that prolonged sitting reduces lower leg microvascular (reactive hyperemia) and macrovascular [flow-mediated dilation (FMD)] vasodilator function. However, these studies have predominately included men, and the effects of sitting in young women are largely unexplored. This becomes important given known sex differences in vascular function. Thus, herein, we assessed popliteal artery reactive hyperemia and FMD before and after a 3-h sitting period in healthy young women (n = 12) and men (n = 8). In addition, resting popliteal artery hemodynamics (duplex Doppler ultrasound) and calf circumference were measured before, during, and after sitting. Resting popliteal artery shear rate was reduced to a similar extent in both groups during the sitting period (women: -48.5 ± 8.4 s-1 and men: -52.9 ± 12.3 s-1, P = 0.45). This was accompanied by comparable increases in calf circumference in men and women (P = 0.37). After the sitting period, popliteal artery FMD was significantly reduced in men (PreSit: 5.5 ± 0.9% and PostSit: 1.6 ± 0.4%, P < 0.001) but not women (PreSit: 4.4 ± 0.6% and PostSit: 3.6 ± 0.6%, P = 0.29). In contrast, both groups demonstrated similar reductions in hyperemic blood flow area under the curve (women: -28,860 ± 5,742 arbitrary units and men: -28,691 ± 9,685 arbitrary units, P = 0.99), indicating impaired microvascular reactivity after sitting. These findings indicate that despite comparable reductions in shear rate during 3 h of uninterrupted sitting, macrovascular function appears protected in some young women but the response was variable, whereas men exhibited more consistent reductions in FMD. In contrast, the leg microvasculature is susceptible to similar sitting-induced impairments in men and women.NEW & NOTEWORTHY We demonstrate that leg macrovascular function was consistently reduced in young men but not young women after prolonged sitting. In contrast, both men and women exhibited similar reductions in leg microvascular reactivity after sitting. These data demonstrate, for the first time, sex differences in vascular responses to prolonged sitting.

Sex differences in vascular function following antioxidant supplementation

Sex differences in vascular function following antioxidant supplementation

Sex-Dependent Impact of OSA on Digital Vascular Function

Indexes of associations between OSA and impaired vascular function are mainly based on small, clinic-based studies of conduit artery function in men with severe sleep apnea. Larger population-based studies show no independent associations or associations in women only. Sex differences in OSA-related mortality may exist, and sex differences in vascular function in subjects with OSA need to be explored. We, therefore, assessed whether OSA is associated with digital vascular function in a large population-based sample and whether this association is influenced by sex. From a population-based cohort of 30,000 subjects aged 30 to 65 years, we examined 479 subjects (mean age, 48 years; 43% women). Oversampling of subjects at high risk of OSA was performed. Sleep apnea was assessed by inhospital polysomnography. Endothelial function was assessed by digital peripheral arterial tonometry and was expressed as the reactive hyperemia index (RHI). OSA was diagnosed in 266 subjects (55.5%). The RHI was significantly lower in subjects with severe OSA than in those without OSA (P = .002). In the multivariate model for RHI, a significant interaction between OSA and sex was found. In sex-specific multivariate linear regression models, adjusting for conventional cardiovascular risk factors, OSA was an independent predictor of a low RHI in women (P = .006) but not in men. The association between OSA and low RHI in women was independent of postmenopausal status. In a large population-based sample of middle-aged subjects, OSA was independently associated with impaired digital vascular function in women only.

Sex-Based Differences in Vascular Function

Cardiovascular disease is the leading cause of morbidity and mortality for both men and women in the USA. However, there are differences between the sexes in age-dependent onset, severity, symptoms and outcomes. Basic research into the causes of sex-dependent differences in cardiovascular disease is ongoing and includes investigation into genetic variation in expression and distribution of receptors for the sex steroids; specificity of natural and synthetic ligands that activate the sex steroid receptors; and intracellular mechanisms that are activated by the receptors in all components of the vessel wall and blood elements, which integrate to regulate vascular tone, vascular repair and remodeling in health and disease. In this era of personalized medicine, basic research into mechanisms of sex differences in vascular function will result in improved prevention, detection and treatment of cardiovascular disease in both men and women.

Intrinsic sex-specific differences in microvascular endothelial cell phosphodiesterases

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 (P(s)) 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, P(s), 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 P(s) did not differ between XY (1.7 +/- 0.2 x 10(-6) cm/s; n = 8) and XX (1.8 +/- 0.1 x 10(-6) cm/s; n = 10) EC. Cilostazol, a PDE3 inhibitor, reduced (11%, P < 0.05) P(s) 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.

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

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.