Diabetes-related sex differences in the brain endothelin system following ischemia in vivo and in human brain endothelial cells in vitro.
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ABSTRACT:
SUBMITTER: Abdul Y
PROVIDER: S-EPMC7508777 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Ischemic stroke is a major cause of death and disability worldwide. Translation into the clinical setting of neuroprotective agents showing promising results in pre-clinical studies has systematically failed. One of the reasons that could explain this failure is that the animal models used to test neuroprotectants do not represent properly the population affected by stroke, as the majority of pre-clinical studies are performed in healthy young male mice. In this regard, we aimed to determine if the response to cerebral ischemia differed depending on age, sex and the presence of comorbidities. Thus, we explored proteomic and transcriptomic changes triggered during the hyperacute phase of cerebral ischemia (by transient intraluminal middle cerebral artery occlusion) in the brain of: (1) young male mice, (2) young female mice, (3) aged male mice and (4) diabetic young male mice. Moreover, we compared the proteomic and transcriptomic changes of each group using an integrative enrichment pathways analysis to disclose key common and exclusive altered proteins, genes and pathways in the first stages of the disease. We found 61 differentially expressed genes (DEG) in male mice, 77 in females, 699 in diabetic and 24 in aged mice. Of these, only 14 were commonly dysregulated in all four groups. The enrichment pathways analysis revealed that the inflammatory response was the biological process with more DEG in all groups of animals, followed by hemopoiesis and lymphoid organ development. Our findings indicate that the response to cerebral ischemia regarding proteomic and transcriptomic changes differs depending on the sex, age and comorbidities, highlighting the importance of incorporating these groups of animals in future stroke research studies.
2022-11-14 | PXD032141 | Pride
Project description:Emerging evidence suggests that renal endothelial function may be altered in ischemia-reperfusion injury. Acute kidney injury is sexually dimorphic, and estrogen protects renal tubular function after experimental ischemic injury. This study tested the hypothesis that during ischemia-reperfusion, estrogen alters glomerular endothelial function to prevent hyperpermeability. Glomerular endothelial cells were exposed to 8-h oxygen-glucose deprivation (OGD) followed by 4- and 8-h reoxygenation-glucose repletion. After 4-h reoxygenation-glucose repletion, transendothelial permeability to Ficoll-70 was reduced, and transendothelial resistance increased, by 17?-estradiol vs. vehicle treatment during OGD (OGD-vehicle: 91.0 ± 11.8%, OGD-estrogen: 102.6 ± 10.8%, P < 0.05). This effect was reversed by coadministration of G protein-coupled receptor 30 (GPR30) antagonist G15 with 17?-estradiol (OGD-estrogen-G15: 89.5 ± 6.9, P < 0.05 compared with 17?-estradiol). To provide preliminary confirmation of this result in vivo, Ficoll-70 was administered to mice 24 h after cardiac arrest and cardiopulmonary resuscitation (CA/CPR). Blood urea nitrogen (BUN) and serum creatinine (SCr) in these mice were elevated within 12 h following CA/CPR and reduced at 24 h by pretreatment with 17?-estradiol (BUN/SCr 17?-estradiol: 34 ± 19/0.2 ± 0.1 vehicle: 92 ± 49/0.5 ± 0.3, n = 8-12, P < 0.05). Glomerular sieving of Ficoll 70 was increased by CA/CPR within 2 h of injury and 17?-estradiol treatment (?; 17?-estradiol: 0.74 ± 0.26 vs. vehicle: 1.05 ± 0.53, n = 14-15, P < 0.05). These results suggest that estrogen reduces postischemic glomerular endothelial hyperpermeability at least in part through GPR30 and that estrogen may regulate post CA/CPR glomerular permeability in a similar fashion in vivo.
| S-EPMC3774263 | biostudies-literature
Project description:Signal transduction and activator of transcription-3 (STAT3) plays an important role in neuronal survival, regeneration and repair after brain injury. We previously demonstrated that STAT3 is activated in brain after cerebral ischemia specifically in neurons. The effect was sex-specific and modulated by sex steroids, with higher activation in females than males. In the current study, we used a proteomics approach to identify downstream proteins affected by ischemia in male and female wild-type (WT) and neuron-specific STAT3 knockout (KO) mice. We established four comparison groups based on the transgenic condition and the hemisphere analyzed, respectively. Moreover, the sexual variable was taken into account and male and female animals were analyzed independently. Results support a role for STAT3 in metabolic, synaptic, structural and transcriptional responses to cerebral ischemia, indeed the adaptive response to ischemia/reperfusion injury is delayed in neuronal-specific STAT3 KO mice. The differences observed between males and females emphasize the importance of sex-specific neuronal survival and repair mechanisms, especially those involving antioxidant and energy-related activities, often caused by sex hormones.
| S-EPMC3325362 | biostudies-literature
Project description:The extent of stroke damage in patients affects the range of subsequent pathophysiological responses that influence recovery. Here we investigate the effect of lesion size on development of new blood vessels as well as inflammation and scar formation and cellular responses within the subventricular zone (SVZ) following transient focal ischemia in rats (n = 34). Endothelin-1-induced stroke resulted in neurological deficits detected between 1 and 7 days (P<0.001), but significant recovery was observed beyond this time. MCID image analysis revealed varying degrees of damage in the ipsilateral cortex and striatum with infarct volumes ranging from 0.76-77 mm3 after 14 days, where larger infarct volumes correlated with greater functional deficits up to 7 days (r = 0.53, P<0.05). Point counting of blood vessels within consistent sample regions revealed that increased vessel numbers correlated significantly with larger infarct volumes 14 days post-stroke in the core cortical infarct (r = 0.81, P<0.0001), core striatal infarct (r = 0.91, P<0.005) and surrounding border zones (r = 0.66, P<0.005; and r = 0.73, P<0.05). Cell proliferation within the SVZ also increased with infarct size (P<0.01) with a greater number of Nestin/GFAP positive cells observed extending towards the border zone in rats with larger infarcts. Lesion size correlated with both increased microglia and astrocyte activation, with severely diffuse astrocyte transition, the formation of the glial scar being more pronounced in rats with larger infarcts. Thus stroke severity affects cell proliferation within the SVZ in response to injury, which may ultimately make a further contribution to glial scar formation, an important factor to consider when developing treatment strategies that promote neurogenesis.
| S-EPMC4029108 | biostudies-literature
Project description:The blood-brain barrier (BBB) is composed of uniquely differentiated brain microvascular endothelial cells (BMEC). Often, it is of interest to replicate these attributes in the form of an in vitro model, and such models are widely used in the research community. However, the BMEC used to create in vitro BBB models de-differentiate in culture and lose many specialized characteristics. These changes are poorly understood at a molecular level, and little is known regarding the consequences of removing BMEC from their local in vivo microenvironment. To address these issues, suppression subtractive hybridization (SSH) was used to identify 25 gene transcripts that were differentially expressed between in vivo and in vitro BMEC. Genes affected included those involved in angiogenesis, transport and neurogenesis, and real-time quantitative polymerase chain reaction (qPCR) verified transcripts were primarily and significantly downregulated. Since this quantitative gene panel represented those BMEC characteristics lost upon culture, we used it to assess how culture manipulation, specifically BMEC purification and barrier induction by hydrocortisone, influenced the quality of in vitro models. Puromycin purification of BMEC elicited minimal differences compared with untreated BMEC, as assessed by qPCR. In contrast, qPCR-based gene panel analysis after induction with hydrocortisone indicated a modest shift of 10 of the 23 genes toward a more 'in vivo-like' gene expression profile, which correlated with improved barrier phenotype. Genomic analysis of BMEC de-differentiation in culture has thus yielded a functionally diverse set of genes useful for comparing the in vitro and in vivo BBB.
| S-EPMC2637221 | biostudies-literature
Project description:We hypothesized that angiotensin (Ang) II hypertensive rats have impaired natriuresis after renal medullary endothelin (ET) B receptor stimulation that would be more evident in male versus female rats. Acute intramedullary infusion of the ET(B) agonist sarafotoxin 6c in normotensive male rats increased sodium excretion from 0.51±0.11 ?mol/min during baseline to 1.64±0.19 ?mol/min (P<0.05) after S6c. After 2 weeks of Ang II infusion (260 ng/kg per minute SC), male rats had an attenuated natriuretic response to S6c of 0.62±0.16 ?mol/min during baseline versus 0.95±0.07 ?mol/min after S6c. In contrast, ET(B)-dependent natriuresis was similar in female hypertensive rats (0.48±0.07 versus 1.5±0.18 ?mol/min; P<0.05) compared with normotensive controls (1.05±0.07 versus 2.14±0.24 ?mol/min; P<0.05). Because ET(A) receptors also mediate natriuresis in normotensive female rats, we examined ET(A) receptor function in female Ang II hypertensive rats. Intramedullary infusion of ET-1 increased sodium excretion in both hypertensive and normotensive female rats, which was partially blocked by the ET(A) antagonist BQ-123. Maximum ET(B) receptor binding in inner medullary membrane preparations was comparable between vehicle and Ang II hypertensive females; however, maximum ET(B) binding was significantly lower in male hypertensive rats (1952±251 versus 985±176 fmol/mg; P<0.05). These results indicate that renal ET(B) function is impaired in male Ang II hypertension attributed, at least in part, to a reduced number of ET(B) binding sites. Furthermore, renal ET receptor function is preserved in female rats during chronic Ang II infusion, suggesting that renal ET receptor function could serve to limit hypertension in females compared with males.
| S-EPMC3141095 | biostudies-literature
Project description:BackgroundIncreased endothelin (ET)-1 expression causes endothelial dysfunction and oxidative stress. Plasma ET-1 is increased in patients with diabetes mellitus. Since endothelial dysfunction often precedes vascular complications in diabetes, we hypothesized that overexpression of ET-1 in the endothelium would exaggerate diabetes-induced endothelial dysfunction.MethodsDiabetes was induced by streptozotocin treatment (55mg/kg/day, i.p.) for 5 days in 6-week-old male wild type (WT) mice and in mice overexpressing human ET-1 restricted to the endothelium (eET-1). Mice were studied 14 weeks later. Small mesenteric artery (MA) endothelial function and vascular remodeling by pressurized myography, reactive oxygen species (ROS) production by dihydroethidium staining and mRNA expression by reverse transcription/quantitative PCR were determined.ResultsEndothelium-dependent vasodilatory responses to acetylcholine of MA were reduced 24% by diabetes in WT ( P < 0.05), and further decreased by 12% in eET-1 ( P < 0.05). Diabetes decreased MA media/lumen in WT and eET-1 ( P < 0.05), whereas ET-1 overexpression increased MA media/lumen similarly in diabetic and nondiabetic WT mice ( P < 0.05). Vascular ROS production was increased 2-fold by diabetes in WT ( P < 0.05) and further augmented 1.7-fold in eET-1 ( P < 0.05). Diabetes reduced endothelial nitric oxide synthase (eNOS, Nos3 ) expression in eET-1 by 31% ( P < 0.05) but not in WT. Induction of diabetes caused a 52% ( P < 0.05) increase in superoxide dismutase 1 ( Sod1 ) and a 32% ( P < 0.05) increase in Sod2 expression in WT but not in eET-1.ConclusionsIncreased expression of ET-1 exaggerates diabetes-induced endothelial dysfunction. This may be caused by decrease in eNOS expression, increase in vascular oxidative stress, and decrease in antioxidant capacity.
| S-EPMC5055737 | biostudies-literature
Project description:We have previously demonstrated that in response to cerebral ischemia (CI), the growth factor angiopoietin-1 (Ang1) and ?5?1 integrin are both induced in cerebral vessels, which likely provide positive signals driving the endogenous angiogenic response and vascular protection after CI. However, the precise relationship between endothelial Ang1 and ?5?1 integrin after CI remains poorly understood. Here, we investigated the effects of the interaction between the Ang1/Tie2 system and ?5?1 integrin on brain endothelial cells (BECs) under cerebral ischemic conditions in vivo and in vitro. Immunofluorescence analysis demonstrated that integrin ?5?1 co-localized with Tie2/phosphorylated Tie2 on cerebral vessels in the penumbra. The in vitro study showed that oxygen-glucose deprivation/restoration (OGD/R) induced the expression of the Ang1 receptor Tie2 on BECs in a manner similar to that for integrin ?5 and Ang1 in response to OGD/R, accompanied by increased activation of Tie2 and its downstream effectors focal adhesion kinase (FAK) and Akt. Knockdown of ?5 integrin markedly suppressed OGD/R-induced Tie2 receptor activation in BECs, while in contrast, priming BECs with Ang1 promoted the expression of ?5 integrin as well as the Tie2 downstream transcription factor Ets-1 in OGD-treated BECs. In line with this, Ets-1 knockdown significantly attenuated Ang1-mediated upregulation of ?5 integrin. Functionally, Ang1 induced cell migration and tube formation of BECs after OGD, but this effect was inhibited by diminishment of the levels of ?5 integrin in BECs. Taken together, our data indicate that the Ang1/Tie2 system cross-talks with integrin ?5?1 in BECs after CI, which may contribute to the endogenous angiogenic vascular protective response following CI.
| S-EPMC6123805 | biostudies-other
Project description:The prevalence of type 2 diabetes mellitus is increasing in both sexes, but men are usually diagnosed at a younger age and lower body fat mass than women. Worldwide, an estimated 17.7 million more men than women have diabetes mellitus. Women appear to bear a greater risk factor burden at the time of their type 2 diabetes diagnosis, especially obesity. Moreover, psychosocial stress might play a more prominent role in diabetes risk in women. Across their lifespan, women experience greater hormone fluctuations and body changes due to reproductive factors than men. Pregnancies can unmask pre-existing metabolic abnormalities, resulting in the diagnosis of gestational diabetes, which appears to be the most prominent risk factor for progression to type 2 diabetes in women. Additionally, menopause increases women's cardiometabolic risk profile. Due to the progressive rise in obesity, there is a global increase in women with pregestational type 2 diabetes, often with inadequate preconceptual care. There are differences between men and women regarding type 2 diabetes and other cardiovascular risk factors with respect to comorbidities, the manifestation of complications and the initiation of and adherence to therapy. Women with type 2 diabetes show greater relative risk of CVD and mortality than men. Moreover, young women with type 2 diabetes are currently less likely than men to receive the treatment and CVD risk reduction recommended by guidelines. Current medical recommendations do not provide information on sex-specific or gender-sensitive prevention strategies and management. Thus, more research on sex differences, including the underlying mechanisms, is necessary to increase the evidence in the future. Nonetheless, intensified efforts to screen for glucose metabolism disorders and other cardiovascular risk factors, as well as the early establishment of prophylactic measures and aggressive risk management strategies, are still required for both men and women at increased risk of type 2 diabetes. In this narrative review we aim to summarise sex-specific clinical features and differences between women and men with type 2 diabetes into risk factors, screening, diagnosis, complications and treatment.
| S-EPMC10163139 | biostudies-literature
Project description:BackgroundA key mechanism thought to underlie Posttraumatic Stress Disorder (PTSD) is enhanced emotional memory consolidation. Recent evidence in healthy controls revealed that women have greater negative memory consolidation following stress relative to men. This study examined emotional memory consolidation in women and men with PTSD, and in trauma-exposed and non-trauma controls to test the hypothesis that emotionally negative memory consolidation would be greater in women with PTSD.MethodOne hundred and forty-seven men and women (47 with PTSD, 49 trauma-exposed controls, and 51 non-trauma controls) completed an emotional memory task where they looked at negative, neutral and positive images from the International Affective Picture System (IAPS). Delayed recall and an intrusive memory diary were completed two days later.ResultsWomen displayed greater recall, and reported more negative intrusive memories than men. A gender x group interaction effect showed that both women with PTSD and trauma-exposed women reported more intrusive memories than women without trauma exposure or men.ConclusionThis study provided preliminary evidence of sex differences in intrusive memories in those with PTSD as well as those with a history of trauma exposure. Future research should include measures of sex hormones to further examine sex differences on memory consolidation in the context of trauma exposure and PTSD.
| S-EPMC6283557 | biostudies-literature