Ovariectomy Reduces Vasocontractile Responses of Rat Middle Cerebral Arteries After Focal Cerebral Ischemia.

ABSTRACT: Effects of sex hormones on stroke outcome are not fully understood. A deleterious consequence of cerebral ischemia is upregulation of vasoconstrictor receptors in cerebral arteries that exacerbate stroke injury. Here, we tested the hypothesis that female sex hormones alter vasocontractile responses after experimental stroke in vivo or after organ culture in vitro, a model of vasocontractile receptor upregulation. Female rats with intact ovaries and ovariectomized (OVX) females treated with 17ß-estradiol, progesterone, or placebo were subjected to transient, unilateral middle cerebral artery occlusion followed by reperfusion (I/R). The maximum contractile response, measured my wire myography, in response to the endothelin B receptor agonist sarafotoxin 6c was increased in female arteries after I/R, but the maximum response was significantly lower in arteries from OVX females. Maximum contraction mediated by the serotonin agonist 5-carboxamidotryptamine was diminished after I/R, with arteries from OVX females showing a greater decrease in maximum contractile response. Contraction elicited by angiotensin II was similar in all arteries. Neither estrogen nor progesterone treatment of OVX females affected I/R-induced changes in endothelin B- and 5-carboxamidotryptamine-induced vasocontraction. These findings suggest that sex hormones do not directly influence vasocontractile alterations that occur after ischemic stroke; however, loss of ovarian function does impact this process.

Transcriptome profiling revealed early vascular smooth muscle cell gene activation following focal ischemic stroke in female rats - comparisons with males.

BACKGROUND: Women account for 60% of all stroke deaths and are more often permanently disabled than men, despite their higher observed stroke incidence. Considering the clinical population affected by stroke, an obvious drawback is that many pre-clinical and clinical studies only investigate young males. To improve therapeutic translation from bench to bedside, we believe that it is advantageous to include both sexes in experimental models of stroke. The aims of this study were to identify early cerebral vascular responses to ischemic stroke in females, compare the differential gene expression patterns with those seen in males, and identify potential new therapeutic targets. RESULTS: Transient middle cerebral artery occlusion (tMCAO) was used to induce stroke in both female and male rats, the middle cerebral arteries (MCAs) were isolated 3 h post reperfusion and RNA was extracted. Affymetrix whole transcriptome expression profiling was performed on female (n = 12) MCAs to reveal differentially expressed genes. In total, 1076 genes had an increased expression and 879 genes a decreased expression in the occluded MCAs as compared with the control MCAs from female rats. An enrichment of genes related to apoptosis, regulation of transcription, protein autophosphorylation, inflammation, oxidative stress, and tissue repair and recovery were seen in the occluded MCA. The high expression genes chosen for qPCR verification (Adamts4, Olr1, JunB, Fosl1, Serpine1, S1pr3, Ccl2 and Socs3) were all shown to be upregulated in the same manner in both females and males after tMCAO (p < 0.05; n = 23). When comparing the differentially expressed genes in female MCAs (occluded and non-occluded) with our previous findings in males after tMCAO, a total of 297 genes overlapped (all groups had 32 genes in common). CONCLUSIONS: The cascades of processes initiated in the vasculature following reperfusion are complex. Dynamic gene expression alterations were observed in the occluded MCAs, and to a less pronounced degree in the non-occluded MCAs. Dysregulation of inflammation and blood-brain barrier breakdown are possible pharmacological targets. The sample of genes (< 1% of the differentially expressed genes) validated for this microarray did not reveal any sex differences. However, sex differences might be observed for other gene targets.

Performance of five cardiotocography classification templates in labor: a cohort study.

OBJECTIVE: New guidelines for the interpretation of cardiotocography (CTG) have been presented by FIGO in 2015 (FIGO-15) and by NICE in 2017 (NICE-17) and 2022 (NICE-22) In Sweden, a previous template from 2009 (SWE-09) was replaced in 2017 (SWE-17).The objective of the study was to compare these five different templates for CTG classification regarding sensitivity, specificity, positive and negative predictive values in identifying neonates with acidemia at birth (cord artery pH <7.10). METHODS: This is a historical cohort study including singleton births in Lund November 2015-February 2016, after spontaneous or induced labor at ≥34 completed gestational weeks with validated umbilical cord acid-base samples.Characteristics of cardiotocographic traces during the last hour before birth were reviewed by two independent assessors blinded to outcome. Each template was then used to classify the CTG as normal, suspicious, or pathological. Traces for which classification differed between the two assessors for any of the templates were assessed by a third assessor. The classification by majority (at least 2 of 3) was used for analyses.Main outcome measures were the sensitivity, specificity, and positive and negative predictive values for each template to identify neonates with cord artery pH <7.10 by the classification pathological. In a secondary analysis, these outcome measures were calculated for the classifications suspicious + pathological together. RESULTS: SWE-09 and NICE-22 had significantly higher sensitivity (both 92%; 95% CI 79-98%) than NICE-17 (68%; 51-82%), FIGO-15 (42%; 26-59%) and SWE-17 (39%; 24-57%) to identify neonates with acidemia by the classification pathological. Specificity was significantly higher for SWE-17 (91%; 88-93%), FIGO-15 (90%; 88-93%) and NICE-17 (78%; 74-81%) than for NICE-22 (63%; 59-67%) and SWE-09 (62%; 58-66%). The positive predictive value of a pathological pattern ranged between 15% (SWE-09 and NICE-22) and 24% (FIGO-15), and negative predictive values between 95% (SWE-17) and 99% (SWE-09 and NICE-22). Combining suspicious and pathological patterns increased the sensitivity and decreased the specificity for all templates. CONCLUSIONS: Current CTG interpretation templates either have low sensitivity to identify fetal acidemia or low specificity. Among current guidelines, NICE 2022 had the highest sensitivity to identify neonates with acidemia and is considered the safest current classification system. Efforts to further improve diagnostic precision are warranted.

Preliminary evidence that blocking the uptake of placenta-derived preeclamptic extracellular vesicles protects the vascular endothelium and prevents vasoconstriction.

Preeclampsia (PE) is a pregnancy syndrome characterized by hypertension and organ damage manifesting after 20 gestational weeks. The etiology is of multifactorial origin, where placental stress causes increased levels of placenta-derived extracellular vesicles (STBEVs) in the maternal circulation, shown to cause inflammation, endothelial activation, vasoconstriction, and anti-angiogenic activity. General endothelial dysfunction is believed to be initiated by endothelial insult during pregnancy that alters vascular function resulting in increased arterial stiffness, cardiac dysfunction, and increased risk of cardiovascular disease later in life. We compared the effect of normal and PE derived STBEVs in vitro on vascular contractility of human subcutaneous arteries using wire myography. Cellular structures of exposed vessels were investigated by transmission electron microscopy. We explored strategies to pharmacologically block the effects of the STBEVs on human vessels. The PE STBEVs caused significantly stronger angiotensin II-mediated contractions and extended structural damage to human subcutaneous arteries compared to normal STBEVs. These negative effects could be reduced by blocking vesicle uptake by endothelial cells, using chlorpromazine or specific antibodies towards the LOX-1 receptor. The therapeutic potential of blocking vesicle uptake should be further explored, to reduce the permanent damage caused on the vasculature during PE pregnancy to prevent future cardiovascular risk.