The impact of sex and gender on heart-brain axis dysfunction: current concepts and novel perspectives.

The heart-brain axis (HBA) recapitulates all the circuits that regulate bidirectional flow of communication between heart and brain. Several mechanisms may underlie the interdependent relationship involving heterogeneous tissues at rest and during specific target organ injury such as myocardial infarction, heart failure, arrhythmia, stroke, mood disorders, or dementia. In-depth translational studies of the HBA dysfunction under single-organ injury should include both male and female animals to develop sex- and gender-oriented prevention, diagnosis, and treatment strategies. Indeed, sex and gender are determining factors as females and males exhibit significant differences in terms of susceptibility to risk factors, age of onset, severity of symptoms, and outcome. Despite most studies having focused on the male population, we have conducted a careful appraisal of the literature investigating HBA in females. In particular, we have (i) analyzed sex-related heart and brain illnesses, (ii) recapitulated the most significant studies simultaneously conducted on cardio- and cerebro-vascular systems in female populations, and (iii) hypothesized future perspectives for the development of a gender-based approach to HBA dysfunction. Although sex- and gender-oriented research is at its infancy, the impact of sex on HBA dysfunction is opening unexpected new avenues for managing the health of female subjects exposed to risk of lifestyle multi-organ disease.

Increased systolic blood pressure associated with hypertriglyceridemia in female Sprague-Dawley rats.

The effect of hyperlipidemia on the cardiovascular system is uncertain in females. The aim of the present study was to determine whether administration of a lipogenic diet alters cardiovascular parameters in female rats. Fifty female Sprague-Dawley rats were assigned into 2 groups of rats receiving a standard or a high-fat, high-sucrose diet (HFHS) for 6 weeks (n = 25 per group). Body mass, blood lipids concentrations, triglycerides clearance, blood pressures (BPs), systolic and diastolic functions, as well as vascular reactivity were assessed at the end of the diet intervention. At termination, body mass was similar between the 2 groups. Fasting blood triglycerides concentration (BTG) was greater in the HFHS group. Triglycerides clearance was impaired in the HFHS group. High-density lipoprotein (HDL) cholesterol concentration was lower in the HFHS group. The early-to-late diastolic filling velocity ratio (E/A) was lower in the HFHS group and negatively associated with BTG. The sensitivity (EC50) of mesenteric arteries to phenylephrine was greater in HFHS and was negatively associated with BTG, but not HDL. Systolic BP was higher in the HFHS group and was positively associated with BTG and HDL. The association between systolic BP and BTG was independent of other lipids measured. In conclusion, hypertriglyceridemia may have increased resistance arteries responsiveness to alpha-agonist and systolic BP in female rats.

Developmental and sex differences in cardiac tolerance to ischemia-reperfusion injury: the role of mitochondria 1.

Age and sex play an essential role in the cardiac tolerance to ischemia-reperfusion injury: cardiac resistance significantly decreases during postnatal maturation and the female heart is more tolerant than the male myocardium. It is widely accepted that mitochondrial dysfunction, and particularly mitochondrial permeability transition pore (MPTP) opening, plays a major role in determining the extent of cardiac ischemia-reperfusion injury. We have observed that the MPTP sensitivity to the calcium load differs in mitochondria isolated from neonatal and adult myocardium, as well as from adult male and female hearts. Neonatal and female mitochondria are more resistant both in the extent and in the rate of mitochondrial swelling induced by high calcium concentration. Our data further suggest that age- and sex-dependent specificity of the MPTP is not the result of different amounts of ATP synthase and cyclophilin D: neonatal and adult hearts, similarly as the male and female hearts, contain comparable amounts of MPTP and its regulatory protein cyclophilin D. We can speculate that the lower sensitivity of MPTP to the calcium-induced swelling may be related to the higher ischemic tolerance of both neonatal and female myocardium.

Mechanistic effect of human umbilical cord blood derived mesenchymal stem cells on the submandibular salivary gland in ovariectomized rats.

We performed this study to understand the effect of human umbilical cord blood derived mesenchymal stem cells (hUCB-MSCs) on the submandibular gland after bilateral ovariectomy. For this, 21 adult female rats were distributed equally among 3 groups: the sham-operated group (SHAM); the ovariectomized group (OVX); and the OVX group that received repeated intravenous injections of the hUCB-MSCs (OVX + hUCB-MSCs). We used reverse transcription - PCR to analyze for the gene expression of AQPs 3, 4, 5, and BMP-6. The cellular localization and expression of human CD105, human CD34, proliferating nuclear antigen (PCNA), single-stranded DNA (ss-DNA), caspase 3, AQP1, and α smooth muscle actin (α-SMA) were determined immunohistochemically. In the OVX group, a significant decrease in the gene expression of AQP3, AQP4, and BMP6, as well as the acinar area % was detected, while area % of granular convoluted tubules (GCTs) showed a significant increase. A significant decrease in area % staining positively for AQP1 and α-SMA was noted. An obvious improvement in the structure of the submandibular gland was demonstrated in the group injected with hUCB-MSCs, as well as a significant increase in the gene expression of AQP3, AQP4, and BMP6. The acinar and GCT area %, as well as the different measured markers, were relatively normal. This demonstrates that E2-deficiency induces structural changes to the submandibular gland. Moreover, a definite amelioration of the structure and function of the submandibular gland was detected after the administration of hUCB-MSCs.

Comparative transcript profiling reveals the mechanism of female sterility associated with seedless Ponkan mandarin (Citrus reticulata Blanco).

Seedlessness is a highly desirable trait in citrus varieties. Sterility is the key determination for seedlessness formation. However, the molecular basis for female sterility in seedless mandarin remains unclear. Thus, a seedless Ponkan mandarin (Citrus reticulata Blanco 'Lipeng No.2'), considered the bud mutation of normal seedy Ponkan, was collected to identify candidate genes involved in seedless variation. Suppression subtractive hybridization (SSH) screened 1091 uniESTs related to seedy and seedless Ponkan (727 singlets and 364 contigs), which mainly governed catalytic activity, transferase activity, and oxygen binding. By using RNA-Seq technology, 106 differentially expressed genes (DEGs) were captured, of which 74 were up-regulated and 32 were down-regulated. Gene Ontology and pathway analysis showed that six DEGs were enriched in the biosynthesis of secondary metabolite, whereas five DEGs were enriched in the signaling of plant hormones. The combined results of SSH and RNA-Seq indicated the importance of amino acid metabolism in seedless Ponkan. Our findings revealed that the mechanism of seedless Ponkan generation may be related to gene regulation, signal cascade, and hormone levels. This study provided a solid foundation for functional gene identification in seedless Ponkan and a good reference for relevant research on molecular mechanisms of female sterility in Ponkan mandarin.

The Z chromosome is enriched for sperm proteins in two divergent species of Lepidoptera.

Genes that promote sexual conflict, such as those with a sex-limited fitness benefit, are expected to accumulate differentially on sex chromosomes relative to autosomes. Few tests of this hypothesis exist for male homogametic (ZZ) taxa, however, and most use RNA expression data to identify such genes. Here, we employ a different identification method by using proteomic analysis of sperm cells to identify genes with a sex-limited benefit. We tested for a bias in genomic location of sperm protein genes in two species of Lepidoptera. An excess of sperm protein genes was identified on the Z chromosomes of both the Carolina sphinx moth (Manduca sexta) and the monarch butterfly (Danaus plexippus). Taking into consideration a Z-autosome fusion in monarchs, we discover that the ancestrally sex-linked portion of the genome is the source of this enrichment, while the newly sex-linked portion still appears similar to autosomes in relative abundance of sperm protein genes. Together, these results point to an enrichment of male-beneficial genes on the Z chromosome and demonstrate the usefulness of proteomic datasets in sexual conflict research.

Molecular mapping of five soybean genes involved in male-sterility, female-sterility.

In soybean, asynaptic and desynaptic mutants lead to abnormal meiosis and fertility reduction. Several male-sterile, female-sterile mutants have been identified and studied in soybean, however, some of these mutants have not been mapped to locations on soybean chromosomes. The objectives of this study were to molecularly map five male-sterile, female-sterile genes (st2, st4, st5, st6, and st7) in soybean and compare the map locations of these genes with already mapped sterility genes. Microsatellite markers were used in bulked segregant analyses to locate all five male-sterile, female-sterile genes to soybean chromosomes, and markers from the corresponding chromosomes were used on F2 populations to generate genetic linkage maps. The st2, st4, st5, st6, and st7 genes were located on molecular linkage group (MLG) B1 (chromosome 11), MLG D1a (chromosome 01), MLG F (chromosome 13), MLG B2 (chromosome 14), and D1b (chromosome 02), respectively. The st2, st4, st5, st6, and st7 genes were flanked to 10.3 (∼ 399 kb), 6.3 (∼ 164 kb), 3.9 (∼ 11.8 Mb), 11.0 (∼ 409 kb), and 5.3 cM (∼ 224 kb), and the flanked regions contained 57, 17, 362, 52, and 17 predicted genes, respectively. Future characterization of candidate genes should facilitate identification of the male- and female-fertility genes, which may provide vital insights on structure and function of genes involved in the reproductive pathway in soybean.

Molecular mapping of three male-sterile, female-fertile mutants and generation of a comprehensive map of all known male sterility genes in soybean.

In soybean, an environmentally stable male sterility system is vital for making hybrid seed production commercially viable. Eleven male-sterile, female-fertile mutants (ms1, ms2, ms3, ms4, ms5, ms6, ms7, ms8, ms9, msMOS, and msp) have been identified in soybean. Of these, eight (ms2, ms3, ms5, ms7, ms8, ms9, msMOS, and msp) have been mapped to soybean chromosomes. The objectives of this study were to (i) locate the ms1, ms4, and ms6 genes to soybean chromosomes; (ii) generate genetic linkage maps of the regions containing these genes; and (iii) develop a comprehensive map of all known male-sterile, female-fertile genes in soybean. The bulked segregant analysis technique was used to locate genes to soybean chromosomes. Microsatellite markers from the corresponding chromosomes were used on F2 populations to generate genetic linkage maps. The ms1 and ms6 genes were located on chromosome 13 (molecular linkage group F) and ms4 was present on chromosome 2 (molecular linkage group D1b). Molecular analyses revealed markers Satt516, BARCSOYSSR_02_1539, and AW186493 were located closest to ms1, ms4, and ms6, respectively. The ms1 and ms6 genes, although present on the same chromosome, were independently assorting with a genetic distance of 73.7 cM. Using information from this study and compiled information from previously published male sterility genes in soybean, a comprehensive genetic linkage map was generated. Eleven male sterility genes were present on seven soybean chromosomes. Four genes were present in two regions on chromosome 2 (molecular linkage group D1b) and two genes were present on chromosome 13 (molecular linkage group F).

Age- and gender-related changes in glucose homeostasis in glucocorticoid-treated rats.

The disruption to glucose homeostasis upon glucocorticoid (GC) treatment in adult male rats has not been fully characterized in older rats or in females. Thus, we evaluated the age- and gender-related changes in glucose homeostasis in GC-treated rats. We injected male and female rats at 3 months and 12 months of age with either dexamethasone (1.0 mg/kg body mass, intraperitoneally) or saline, daily for 5 days. All of the GC-treated rats had decreased body mass and food intake, and adrenal hypotrophy. Increased glycemia was observed in all of the GC-treated groups and only the 3-month-old female rats were not glucose intolerant. Dexamethasone treatment resulted in hyperinsulinemia and hypertriacylglyceridemia in all of the GC-treated rats. The glucose-stimulated insulin secretion (GSIS) was higher in all of the dexamethasone-treated animals, but it was less pronounced in the older animals. The ß-cell mass was increased in the younger male rats treated with dexamethasone. We conclude that dexamethasone treatment induces glucose intolerance in both the 3- and 12-month-old male rats as well as hyperinsulinemia and augmented GSIS. Three-month-old female rats are protected from glucose intolerance caused by GC, whereas 12-month-old female rats developed the same complications that were present in 3- and 12-month-old male rats.

Core temperature is a greater influence than endogenous 17ß-estradiol on the exercise-induced accumulation of myocardial heat shock protein mRNA.

Female rats typically do not show significant increases in myocardial Hsp70 after exercise unless trained (exercise over days or weeks). 17ß-Estradiol (E2) has been linked to this inhibition, but it varies considerably over the rodent estrus cycle. Consequently, we examined whether the inhibitory effects of endogenously produced E2 (measured immediately pre-exercise) were acute in exercised female Sprague-Dawley rats (60 min treadmill running at 30 m·min(-1)). Myocardial hsp70-1 and hsp70-2 mRNA were measured 30 min post-exercise, and their expression was inversely correlated with pre-exercise plasma Ε2 ( hsp70-1 mRNA, r(2) = 0.308, p = 0.011; hsp70-2 mRNA, r(2) = 0.238, p = 0.029). However, hsp70-1 and hsp70-2 mRNA exhibited much stronger correlations with core temperature achieved during exercise (r(2) = 0.812, p = 0.000; and r(2) = 0.738, p = 0.000, respectively). Consequently, although endogenous Ε2 in gonadally intact female rats may attenuate myocardial hsp70 mRNA accumulation, suggesting a reason why training maximizes this response in females, core temperature during exercise is still a greater stimulus to this response.