Gender differences in small intestinal perfusion following trauma hemorrhage: the role of endothelin-1

Although gender differences in intestinal perfusion exist following trauma-hemorrhage (T-H), it remains unknown whether endothelin-1 (ET-1) plays any role in these dimorphic responses. To study this, male, proestrus female (female), and 17 beta-estradiol (E2)-treated male rats underwent midline laparotomy, hemorrhagic shock (blood pressure 40 mmHg, 90 min), and resuscitation (Ringer lactate, 4X shed blood volume, 1 h). Two hours thereafter, intestinal perfusion flow (IPF) was measured using isolated intestinal perfusion. The IPF in sham-operated males was significantly lower than those in other groups and decreased markedly following T-H. In contrast, no significant decrease in IPF was observed in females and E2 males following T-H. The lower IPF in sham-operated males was significantly elevated by ET(A) receptor antagonist (BQ-123) administration and was similar to that seen in sham-operated females. The decreased IPF in males after T-H was also attenuated by BQ-123 administration. The intestinal ET-1 levels in sham-operated males were significantly higher than in other groups. Although plasma and intestinal ET-1 levels increased significantly after T-H in all groups, they were highest in males. Plasma E2 levels in females and E2 males were significantly higher than in males; however, they were not affected by T-H. There was a negative correlation between plasma ET-1 and E2 following T-H. Thus ET-1 appears to play an important role in intestinal perfusion failure following T-H in males. Because E2 can modulate this vasoconstrictor effect of ET-1, these findings may partially explain the previously observed salutary effect of estrogen in improving intestinal perfusion following T-H in males.     

Gender dimorphic tissue perfusion response after acute hemorrhage and resuscitation: role of vascular endothelial cell function

Proestrous female rodents are protected from the deleterious effects of trauma-hemorrhage that are observed in males. We hypothesized that the gender dimorphic outcome after trauma-hemorrhage might be related to gender differences in endothelial function and organ perfusion under such conditions. Male and cycle-matched proestrous female Sprague-Dawley rats underwent a midline laparotomy, hemorrhagic shock (40 mmHg for approximately 90 min), and resuscitation (Ringer lactate, 4x shed blood volume over 60 min). Various parameters were measured 2 h after completion of resuscitation. In the first set of animals, the left ventricle was cannulated and heart performance (maximal rate of left ventricular pressure increase) as well as cardiac output and organ perfusion rates were determined with (85)Sr microspheres. In the second set of animals, aortic vessel rings were harvested and relaxation in response to acetylcholine and nitroglycerin was measured. In the third set of animals, in situ isolated small intestine was perfused to measure the response of the splanchnic vessel bed to acetylcholine and nitroglycerin. After trauma-hemorrhage and resuscitation, females maintained cardiac output and demonstrated increased splanchnic and cardiac perfusion compared with males. Moreover, female intestines did not manifest the endothelial dysfunction that was observed in male intestines after hemorrhagic shock. We conclude that proestrous females show improved endothelial function and tissue perfusion patterns after hemorrhagic shock and that this gender-specific response might be a potential mechanism contributing to the beneficial effects of the proestrus stage under such conditions.     

Gender differences in ischemia-reperfusion-induced microcirculatory and epithelial dysfunctions in the small intestine

Female sex hormones have been reported to preserve endothelial integrity and to reduce inflammation. However, gender-related differences in the intestinal mucosal barrier function during compromised perfusion after ischemia and transplantation have not been defined. Herein, we applied intravital microscopy to determine the mucosal epithelial and intestinal microcirculatory responses in ileal villus and longitudinal muscle layers in a murine model of 30-min intestinal ischemia and 90-min reperfusion. In male animals, the entire reperfusion period was characterized by a significantly increased epithelial permeability. This was associated with an early leukocytic inflammatory response and late alterations in functional capillary density, capillary red blood cell velocity and mitochondrial redox state. In contrast, the female intestine exhibited a delayed increase in epithelial permeability during postischemic reperfusion. This was associated with a late leukocytic inflammatory response which did not affect the microcirculatory function. Nonetheless, at the end of the 90-min reperfusion period, the neutrophilic infiltration and structural mucosal disintegration in the female intestine were found to be pronounced to a similar extent as in the male intestine. These results suggest that in small intestinal ischemia-reperfusion the leukocytic inflammatory response and microcirculatory dysfunction develop more rapidly and are initially more pronounced in males, but the hormonal status in females is not capable of preventing the final manifestations of reperfusion injury.     

Gender differences in right ventricular function in patients with non-ischaemic cardiomyopathy

Aim

To evaluate sex-related differences in right ventricular (RV) function, assessed with cardiac magnetic resonance imaging, in patients with stable non-ischaemic dilated cardiomyopathy.

Methods

Prospective multicentre study. We included 71 patients (38 men) and 14 healthy volunteers.

Results

Mean age was 60.9 ± 12.2 years. Men presented higher levels of haemoglobin and white blood cell counts than women, and performed better in cardiopulmonary stress testing. A total of 24 patients (12 women) presented severe left ventricular (LV) systolic dysfunction, 32 (13 female) moderate and 15 (8 women) mild LV systolic dysfunction. In the group with severe LV systolic dysfunction, average right ventricular ejection fraction (RVEF) was normal in women (52 ± 4 %), whereas it was reduced in men (39 ± 3 %) p = 0.035. Only one woman (8 %) had severe RV systolic dysfunction (RVEF < 35 %) compared with 6 men (50 %) p < 0.001. In patients with moderate and mild LV dysfunction , the mean RVEF was normal in both men and women. In the 14 healthy volunteers, the lowest value of RVEF was 48 % and mean RVEF was normal in women (56 ± 2 %) and in men (51 ±  1 %), p = 0.08.

Conclusions

In patients with dilated cardiomyopathy, RV systolic dysfunction is found mainly in male patients with severe LV systolic dysfunction.     

Gender differences in upper airway compliance during NREM sleep: role of neck circumference.

It has been proposed that the gender difference in sleep apnea prevalence is related to gender differences in upper airway structure and function. We hypothesized that men would have smaller retropalatal cross-sectional area and higher compliance during sleep compared with women. Using upper airway imaging, we measured upper airway cross-sectional area and retropalatal compliance in wakefulness and non-rapid eye movement (NREM) sleep in 15 men and 15 women without sleep-disordered breathing. Cross-sectional area at the beginning of inspiration tended to be larger in men compared with women in both wakefulness [194.5 +/- 21.3 vs. 138.8 +/- 12.0 (SE) mm(2)] and NREM sleep (111.1 +/- 17.6 vs. 83.3 +/- 11.9 mm(2); P = 0.058). There was no significant difference, however, after correction for body surface area. Retropalatal compliance also tended to be higher in men during both wakefulness (5.9 +/- 1.4 vs. 3.1 +/- 1.4 mm(2)/cmH(2)O; P = 0.006) and NREM sleep (12.6 +/- 2.7 vs. 4.7 +/- 2.6 mm(2)/cmH(2)O; P = 0.055). However, compliance was similar in men relative to women after correction for neck circumference. We conclude that the gender difference in retropalatal compliance is more accurately attributed to differences in neck circumference between the genders.     

Gender differences in depression

Depression is twice as common in women as in men, although some concern has been raised in terms of misdiagnosing depression in men. The incidence of depression in women varies during the life span. The peak incidence during childbearing years appears to be associated with cyclic hormonal changes. Women also present with reproductive -specific mood disorders: pre-menstrual dysphoric disorder (PMDD), depression in pregnancy, postpartal mood disorder (PDD) and perimenopausal depressive disorder. Gender differences were repeatedly observed in response to antidepressant medication. Premenopausal women appear to respond poorly and to show low tolerability to TCAs, but they tend to show greater responsiveness to the SSRIs. In contrast, men and postmenopausal women can respond equally to the TCAs and SSRIs. These differences are contributed to gender differences in pharmacokinetics of antidepressants and to the influence of menstrual cycle. These findings suggest the need for a gender-specific approach to the evaluation and management of depression.     

Permanent jejunal fistula: promising method for obtaining small intestinal chyme without disturbing intestinal function

Accurate information on changes in small intestinal microflora in dogs is rather limited because of difficulties in obtaining samples of small intestinal chyme. In the study reported here, intussuscepted nipple valves were surgically placed into the jejunum of seven laboratory beagles to obtain intestinal juice samples. The influence of the fistula on intestinal motility was determined by use of barium-impregnated polyethylene spheres (BIPS) and on microflora by use of bacterial culturing. The BIPS were fed two weeks before surgery and again five weeks after surgery. Bacterial samples were collected before (fecal samples), during (small intestinal samples) and 11 weeks after surgery. There were no surgical complications, and the animals tolerated the fistula well. Mean orocolic transit percentage was 93% before and 83% after surgery, and notable changes in gastrointestinal motility were not seen, except in one dog. The surgery did not markedly alter the bacterial flora in feces. Microflora did change in small intestinal samples; however, methodologic factors may explain most of these differences. In conclusion, the nipple valve is a promising method that creates easy and safe long-term access to the jejunum and appears not to have an influence on intestinal function.     

Gender differences in landmark learning for virtual navigation: the role of distance to a goal

We used a new virtual program in two experiments to prepare subjects to perform the Morris water task (www.nesplora.com). The subjects were Psychology students; they were trained to locate a safe platform amidst the presence of four pinpoint landmarks spaced around the edge of the pool (i.e., two landmarks relatively near the platform and two landmarks relatively distant away from it). At the end of the training phase, we administered one test trial without the platform and recorded the amount of time that the students had spent in the platform quadrant. In Experiment 1, we conducted the test trial in the presence of one or two of the distant landmarks. When only one landmark was present during testing, performance fell to chance. However, the men outperformed the women when the two distant landmarks were both present. Experiment 2 replicated the previous results and extended it by showing that no sex differences exist when the searching process is based on the near landmarks. Both the men and the women had similarly good performances when the landmarks were present both individually and together. When present together, an addition effect was found. Far landmark tests favor configural learning processes, whereas near landmark tests favor elemental learning. Our findings suggest that other factors in addition to the use of directional cues can underlie the sex differences in the spatial learning process. Thus, we expand upon previous research in the field.     

Gender differences in adiponectin modulation of cardiac remodeling in mice deficient in endothelial nitric oxide synthase

Left ventricular hypertrophy (LVH) is a risk factor for cardiovascular disease, a leading cause of death. Alterations in endothelial nitric oxide synthase (eNOS), an enzyme involved in regulating vascular tone, and in adiponectin, an adipocyte‐derived secretory factor, are associated with cardiac remodeling. Deficiency of eNOS is associated with hypertension and LVH. Adiponectin exhibits vaso‐protective, anti‐inflammatory, and anti‐atherogenic properties. We hypothesized that increased levels of adiponectin would alleviate cardiac pathology resulting from eNOS deficiency, while decreased levels of adiponectin would exacerbate the pathology. Male and female mice, deficient in eNOS, and either lacking or over‐expressing adiponectin, were fed high fat diet (HFD) or normal chow. Cardiac magnetic resonance imaging was performed to serially assess heart morphology and function up to 40 weeks of age. Thirty‐two weeks of HFD feeding led to significantly greater LV mass in male mice deficient in eNOS and either lacking or over‐expressing adiponectin. Heart function was significantly reduced when the mice were deficient in either eNOS, adiponectin or both eNOS and adiponectin; for female mice, heart function was only reduced when both eNOS and adiponectin were lacking. Thus, while over‐expression of adiponectin in the eNOS deficient HFD fed male mice preserved function at the expense of significantly increased LV mass, female mice were protected from decreased function and increased LVH by over‐expression of adiponectin. Our results demonstrate a sexual dimorphism in response of the heart to alterations in eNOS and adiponectin during high fat feeding and suggest that adiponectin might require eNOS for some of its metabolic effects. J. Cell. Biochem. 113: 3276–3287, 2012. © 2012 Wiley Periodicals, Inc.     

Gender differences in chronic alcoholism: EEG analysis

Comparative analysis of spatial organization of cortical biopotentials of men (n = 120) and women (n = 75) suffering from alcoholism and persons without addiction to alcohol (control groups) was carried out. Gender differences in the EEG spatial parameters under study (linear spatial synchronization in the brain cortex, non-linear spatial disorder, EEG coherence, and spectral power) were shown to be markedly less pronounced between the control groups (68 women and 85 men) than between the alcohol addicts. The obtained data allow us to explain the known fact of more serious and "malignant" character of alcoholism in women than in men in terms of neurophysiology. In alcoholics, the synchronization of low-frequency oscillations (delta and theta) was higher, whereas the synchronization of the higher-frequency spectrum part (beta1 and beta2) was lower in women than in men. This fact can be a neurophysiological basis of more progredient inhibitory-degenerative processes in women.     

Gender differences in morningness-eveningness preference

Morningness-eveningness preference (morning-, intermediate-, evening-type) or circadian typology is the individual difference that most clearly explains the variations in the rhythmic expression of biological or behavioral patterns. The aim of this study was to analyze gender difference in morningness-eveningness preference using the Horne and Ostberg questionnaire in the largest university student population selected so far (N = 2135), with an age range 18-30 yr. Morningness-eveningness questionnaire (MEQ) score distribution closely correlated to the normal curve (range 17-78, mean = 48.25; SD = 10.11), with 338 (15.84%) morning-types, 1273 (59.62%) intermediate-types, and 524 (24.54%) evening-types. The men and women differed significantly in their mean scores (p < 0.0001) and distribution per circadian typology (p < 0.00001), with the men presenting a more pronounced eveningness preference. Three factors were identified by factor analysis: time of greatest efficiency (I), sleep time/sleep phase (II), awakening time/sleep inertia (III). The MEQ items sensitive to gender differences were essentially those included in factor I and factor II. The results are discussed in relation to recent models of circadian regulation of the sleep-wake cycle.     

Gender differences in Parkinson's disease

Because estrogen has numerous effects on dopamine neurotransmission, many researchers are interested in its possible use to either slow the progression or reduce the risk of Parkinson's disease (PD). The incidence of PD is greater in men than in women. Gender differences in neurotoxicity have been observed, and basic research in experimental animals indicates that estrogen protects neurons from various forms of injury. However, the results of retrospective surveys of the neuroprotective effects of estrogen replacement in PD have been mixed, with some showing no effect on risk and others showing a reduction in risk. A mildly significant gender difference in disability and quality-of-life reporting has been noted, with women citing greater disability and reduced quality of life. Gender differences have been shown in response to treatment of PD, for example, in how levodopa is metabolized-women have greater levodopa bioavailability. In the Parkinson's Disease on Estrogen Therapy Replacement in the Menopause Years (POETRY) study, participants were found to have improved scores on the Unified Parkinson Disease Rating Scale. Based on the POETRY results, it is hypothesized that estrogen replacement therapy (ERT) may lead to improvement in PD symptoms and provide an opportunity to reduce the dosage of antiparkinsonian medication in women.     

The role of sphingosine-1-phosphate in endothelial barrier function

Loss of endothelial barrier function is implicated in the etiology of metastasis, atherosclerosis, sepsis and many other diseases. Studies suggest that sphingosine-1-phosphate (S1P), particularly HDL-bound S1P (HDL–S1P) is essential for endothelial barrier homeostasis and that HDL–S1P may be protective against the loss of endothelial barrier function in disease. This review summarizes evidence providing mechanistic insights into how S1P maintains endothelial barrier function, highlighting the recent findings that implicate the major S1P carrier, HDL, in the maintenance of the persistent S1P-signaling needed to maintain endothelial barrier function. We review the mechanisms proposed for HDL maintenance of persistent S1P-signaling, the evidence supporting these mechanisms and the remaining fundamental questions.     

Circadian regulation of cardiovascular function: a role for vasoactive intestinal peptide

The circadian system, driven by the suprachiasmatic nucleus (SCN), regulates properties of cardiovascular function. The dysfunction of this timing system can result in cardiac pathology. The neuropeptide vasoactive intestinal peptide (VIP) is crucial for circadian rhythms in a number of biological processes including SCN electrical activity and wheel running behavior. Anatomic evidence indicates that SCN neurons expressing VIP are well positioned to drive circadian regulation of cardiac function through interactions with the autonomic centers. In this study, we tested the hypothesis that loss of VIP would result in circadian deficits in heart rate (HR) and clock gene expression in cardiac tissue. We implanted radiotelemetry devices into VIP-deficient mice and wild-type (WT) controls and continuously recorded HR, body temperature, and cage activity in freely moving mice. Under light-dark conditions, VIP-deficient mice displayed weak rhythms in HR, body temperature, and cage activity, with onsets that were advanced in phase compared with WT mice. Similarly, clock gene expression in cardiac tissue was rhythmic but phase advanced in mutant mice. In constant darkness, the normal circadian rhythms in HR were lost in VIP-deficient mice; however, most mutant mice continued to exhibit circadian rhythms of body temperature with shortened free-running period. The loss of VIP altered, but did not abolish, autonomic regulation of HR. Analysis of the echocardiograms did not find any evidence for a loss of cardiac function in VIP-deficient mice, and the size of the hearts did not differ between genotypes. These results demonstrate that VIP is an important regulator of physiological circadian rhythmicity in the heart.     

Hypoxia‐induced endothelial secretion of macrophage migration inhibitory factor and role in endothelial progenitor cell recruitment

Macrophage migration inhibitory factor (MIF) is a pleiotropic inflammatory cytokine that was recently identified as a non‐cognate ligand of the CXC‐family chemokine receptors 2 and 4 (CXCR2 and CXCR4). MIF is expressed and secreted from endothelial cells (ECs) following atherogenic stimulation, exhibits chemokine‐like properties and promotes the recruitment of leucocytes to atherogenic endothelium. CXCR4 expressed on endothelial progenitor cells (EPCs) and EC‐derived CXCL12, the cognate ligand of CXCR4, have been demonstrated to be critical when EPCs are recruited to ischemic tissues. Here we studied whether hypoxic stimulation triggers MIF secretion from ECs and whether the MIF/CXCR4 axis contributes to EPC recruitment. Exposure of human umbilical vein endothelial cells (HUVECs) and human aortic endothelial cells (HAoECs) to 1% hypoxia led to the specific release of substantial amounts of MIF. Hypoxia‐induced MIF release followed a biphasic behaviour. MIF secretion in the first phase peaked at 60 min. and was inhibited by glyburide, indicating that this MIF pool was secreted by a non‐classical mechanism and originated from pre‐formed MIF stores. Early hypoxia‐triggered MIF secretion was not inhibited by cycloheximide and echinomycin, inhibitors of general and hypoxia‐inducible factor (HIF)‐1α‐induced protein synthesis, respectively. A second phase of MIF secretion peaked around 8 hrs and was likely due to HIF‐1α‐induced de novo synthesis of MIF. To functionally investigate the role of hypoxia‐inducible secreted MIF on the recruitment of EPCs, we subjected human AcLDL⁺ KDR⁺ CD31⁺ EPCs to a chemotactic MIF gradient. MIF potently promoted EPC chemotaxis in a dose‐dependent bell‐shaped manner (peak: 10 ng/ml MIF). Importantly, EPC migration was induced by supernatants of hypoxia‐conditioned HUVECs, an effect that was completely abrogated by anti‐MIF‐ or anti‐CXCR4‐antibodies. Thus, hypoxia‐induced MIF secretion from ECs might play an important role in the recruitment and migration of EPCs to hypoxic tissues such as after ischemia‐induced myocardial damage.