Search

This study investigated the middle cerebral artery blood velocity (MCAv) response to constant work-rate moderate-intensity cycling exercise in 21 children (9.3 ± 0.8 yr), 17 adolescents (12.3 ± 0.4 yr), and 20 young adults (23.6 ± 2.4 yr). Participants completed an incremental ramp test to exhaustion on a cycle ergometer to determine maximal oxygen uptake and gas exchange threshold (GET) before completing three 6-min transitions at a moderate intensity (90% GET) on separate visits. On each visit, bilateral MCAv was measured by transcranial Doppler ultrasonography and breath-by-breath end-tidal carbon dioxide ([Formula: see text]) via a metabolic cart. Data were ensemble-averaged for each participant and analyzed using a monoexponential model. Absolute MCAv was significantly higher throughout exercise in children and adolescents compared with adults ( P < 0.001). Children had a significantly lower relative increase in MCAv from baseline (∼12%) compared with adolescents (∼20%) and adults (∼18%, P < 0.040). All adolescents and adults had a monoexponential rise in MCAv and [Formula: see text], but this was observed in only eight children. Children and adolescents had a significantly faster MCAv time constant (τ, 12 ± 6 and 14 ± 8 s, respectively) compared with adults (27 ± 9 s, P < 0.001). MCAv τ was positively associated with faster [Formula: see text] τ in adolescents ( r = 0.70, P = 0.002) but not in children ( r = -0.20, P = 0.640). Time- and amplitude-based response parameters of MCAv kinetics were significantly associated with [Formula: see text] kinetics in adults ( r = 0.50-0.74, P ≤ 0.025), but not in children ( r = -0.19 to -0.48, P > 0.227). These findings suggest that the transition from childhood to adulthood impacts the MCAv response to exercise and the relationships between [Formula: see text] and MCAv kinetics during exercise. NEW & NOTEWORTHY This is the first study to find that children have smaller increases in Δ%MCAv (∼12%) during moderate-intensity exercise compared with adolescents and adults (∼18%-20%). Furthermore, MCAv kinetics were significantly faster in children and adolescents, compared with adults. MCAv kinetic responses were significantly and positively associated with [Formula: see text] kinetics in adults, but not in children. These novel data also suggest that the regulatory role of [Formula: see text] on MCAv during exercise begins to strengthen during adolescence.

Sirtuin 3 has been shown to regulate endothelial function and coronary flow reserve in mice. Knockout of SIRT3 reduced endothelial nitric oxide synthase expression in the mouse hearts. In this study, we investigate whether endothelial SIRT3 regulates vascular function and myogenic responses in distal intramural branches of the left anterior descending coronary artery (CA) and middle cerebral artery (MCA) of mice. Both male and female endothelial SIRT3 knockout (SIRT3 EC KO) mice and control SIRT3 LoxP mice were used and CA and MCA were dissected and mounted in a myograph system. The myogenic response was evaluated by measuring changes in inner diameter in response to 20 mmHg stepwise increases in intraluminal pressure in PSS (active diameter) and Ca2 + -free PSS (passive diameter). Acetylcholine (Ach)-induced endothelial-dependent relaxation (EDR) and sodium nitroprusside (SNP)-induced endothelial-independent relaxation (EIR) were examined. Our results showed that the myogenic responses were significantly impaired in both the CA and MCA of SIRT3 EC KO mice. Furthermore, female mice had worsened myogenic response in MCA. In CA, EDR was abolished in both male and female SIRT3 EC KO mice. Intriguingly, EIR was only reduced in the female mice. In MCA, EDR was reduced in male SIRT3 EC KO mice, whereas EIR was decreased in both male and female mice. Female SIRT3 EC KO mice had profound dysfunction in CA, whereas male mice exhibited more dysfunction in MCA. These data revealed a sex and organ-specific role of endothelial SIRT3 in vascular function and myogenic responses. Our study suggests that endothelial SIRT3 is necessary for maintaining vascular function and blood flow autoregulation., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

The long-term consequences of electronic cigarette (Ecig) use in humans are not yet known, but it is known that Ecig aerosols contain many toxic compounds of concern. We have recently shown that Ecig exposure impairs middle cerebral artery (MCA) endothelial function and that it takes 3 days for MCA reactivity to return to normal. However, the sources contributing to impairment of the endothelium were not investigated. We hypothesized that the increased levels of oxidative stress markers in the blood are correlated with impaired MCA reactivity. We used electron paramagnetic resonance (EPR) spectroscopy to examine plasma from 4-month-old male Sprague-Dawley rats that were exposed to either air (n = 5) or 1 h Ecig exposure, after which blood samples were collected at varying times after exposure (i.e., 1-4, 24, 48 and 72 h postexposure, n = 4 or 5 in each time group). The EPR analyses were performed using the redox-sensitive hydroxylamine spin probe 1-hydroxy-3-carboxymethyl-2,2,5,5-tetramethyl-pyrrolidine (CMH) to measure the level of reactive oxidant species in the plasma samples. We found that EPR signal intensity from the CM • radical was significantly increased in plasma at 1-4, 24 and 48 h (P < 0.05, respectively) and returned to control (air) levels by 72 h. When evaluating the EPR results with MCA reactivity, we found a significant negative correlation (Pearson's P = 0.0027). These data indicate that impaired cerebrovascular reactivity resulting from vaping is associated with the oxidative stress level (measured by EPR from plasma) and indicate that a single 1 h vaping session can negatively influence vascular health for up to 3 days after vaping. HIGHLIGHTS: What is the central question of this study? Does the time course of oxidative stress triggered by electronic cigarette exposure follow the cerebral vascular dysfunction? What is the main finding and its importance? Electron paramagnetic resonance analysis shows that the oxidative stress induced after a single 1 h exposure to electronic cigarette aerosol takes ≤72 h to return to normal, which mirrors the time course for vascular dysfunction in the middle cerebral artery that we have reported previously., (© 2024 The Author(s). Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Vascular aging influences hemodynamics, elevating risks for vascular diseases and dementia. We recently demonstrated that knockout (KO) of Dusp5 enhances cerebral and renal hemodynamics and cognitive function. This improvement correlates with elevated pPKC and pERK1/2 levels in the brain and kidneys. Additionally, we observed that Dusp5 KO modulates the passive mechanical properties of cerebral and renal arterioles, associated with increased myogenic tone at low pressure, enhanced distensibility, greater compliance, and reduced stiffness. The present study evaluates the structural and mechanical properties of the middle cerebral artery (MCA) in Dusp5 KO rats. We found that vascular smooth muscle cell layers and the collagen content in the MCA wall are comparable between Dusp5 KO and control rats. The internal elastic lamina in the MCA of Dusp5 KO rats exhibits increased thickness, higher autofluorescence intensity, smaller fenestrae areas, and fewer fenestrations. Despite an enhanced myogenic response and tone of the MCA in Dusp5 KO rats, other passive mechanical properties, such as wall thickness, cross-sectional area, wall-to-lumen ratio, distensibility, incremental elasticity, circumferential wall stress, and elastic modulus, do not significantly differ between strains. These findings suggest that while Dusp5 KO has a limited impact on altering the structural and mechanical properties of MCA, its primary role in ameliorating hemodynamics and cognitive functions is likely attributable to its enzymatic activity on cerebral arterioles. Further research is needed to elucidate the specific enzymatic mechanisms and explore potential clinical applications in the context of vascular aging., (© 2024. The Author(s), under exclusive licence to American Aging Association.)

A decrease in serum sodium ion concentration below 135 mmol L -1 is usually accompanied by a decrease in plasma osmolality (hypoosmotic hyponatremia) and leads to the disorder of intracranial homeostasis mainly due to cellular swelling. Recently, using an in vitro model of hypoosmotic hyponatremia, we have found that a decrease in sodium ion concentration in the perfusate to 121 mmol L -1 relaxes the isolated rat middle cerebral artery (MCA). The aim of the present study was to explore the mechanism responsible for this relaxation. Isolated, pressurized, and perfused MCAs placed in a vessel chamber were subjected to a decrease in sodium ion concentration to 121 mmol L -1 . Changes in the diameter of the vessels were monitored with a video camera. The removal of the endothelium and inhibition of nitric oxide-dependent signaling or the reverse mode sodium-calcium exchanger (NCX) were used to study the mechanism of the dilation of the vessel during hyponatremia. The dilation of the MCA (19 ± 5%, p < 0.005) in a low-sodium buffer was absent after removal of the endothelium or administration of the inhibitor of the reverse mode of sodium-calcium exchange and was reversed to constriction after the inhibition of nitric oxide (NO)/cGMP signaling. The dilation of the middle cerebral artery of the rat in a 121 mmol L - 1 Na + buffer depends on NO signaling and reverse mode of sodium-calcium exchange. These results suggest that constriction of large cerebral arteries with impaired NO-dependent signaling may be observed in response to hypoosmotic hyponatremia., (© 2022. The Author(s).)

Growing evidence indicates that perivascular tissue is critical to modulate vessel function. We hypothesized that the arachnoid membrane surrounding middle cerebral artery (MCA) regulates its function via sphingosine-1-phosphate (S1P)-induced vasoconstriction. The MCA from 3- to 9-month-old male and female wild-type (Oncine France 1 and C57BL/6) mice and sphingosine kinase 2 knockout (SphK2-/-) mice in the C57BL/6 background was mounted in pressure myographs with and without arachnoid membrane. Raman microspectroscopy and imaging were used for in situ detection of S1P. The presence of arachnoid tissue was associated with reduced external and lumen MCA diameters, and with an increase in basal tone regardless of sex and strain background. Strong S1P-positive signals were detected in the arachnoid surrounding the MCA wall in both mice models, as well as in a human post-mortem specimen. Selective S1P receptor 3 antagonist TY 52156 markedly reduced both MCA vasoconstriction induced by exogenous S1P and arachnoid-dependent basal tone increase. Compared to 3-month-old mice, the arachnoid-mediated contractile influence persisted in 9-month-old mice despite a decline in arachnoid S1P deposits. Genetic deletion of SphK2 decreased arachnoid S1P content and vasoconstriction. This is the first experimental evidence that arachnoid membrane regulates the MCA tone mediated by S1P.

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 17β-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., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Cannabinoids are reported to regulate cardiovascular functions. Cannabinoid receptors 1 (CB1Rs) are widely expressed in both the neuronal system and vascular system, but the contribution of CB1Rs in vascular smooth muscle (CB1R SM ) to cardiovascular functions is not clear yet. In this research, we analyzed the effects of CB1R SM on blood pressure, vasoconstriction, and vasodilation abilities by using conditionally CB1R knockout mice (CB1R SMKO ). The results show no significant difference in basal blood pressure between the conscious CB1R SMKO and control mice, indicating that CB1R SM is not essential for basal blood pressure maintenance. The constriction of the CB1R SMKO mesenteric artery in vitro was not significantly altered compared with that of the control mice. In contrast, the relaxation to CB1R agonist 2-AG or WIN55212-2 was decreased in CB1R SMKO vessels, suggesting that activation of CB1R SM mediates the vasodilation effect of cannabinoids. Ischemia stroke mouse model was used to further identify the potential function of CB1R SM in pathological conditions, and the results showed that the infarct volume in CB1R SMKO mice is significantly increased compared with the control littermates. These results suggest that vascular CB1R may not play a central role in basal vascular health maintenance but is protective in ischemia states, such as stroke. The protection function may be mediated, at least partly, by the relaxation effect of CB1R SM -dependent activities of endocannabinoids., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aging is associated with hypertension and brain blood flow dysregulation, which are major risk factors for cardiovascular and neurodegenerative diseases. Structural remodeling, endothelial dysfunction, or hypercontractility of resistance vessels may cause increased total peripheral resistance and hypertension. Recent studies showed that G protein- and RhoA/Rho-kinase pathways are involved in increased mean arterial pressure (MAP) and arterial tone in middle-aged mice. We aimed to characterize the age-dependent changes in the vascular proteome in normal laboratory mice using mass spectrometry and bioinformatics analyses on middle cerebral arteries and mesenteric resistance arteries from young (3 months) vs. middle-aged (14 months) mice. In total, 31 proteins were significantly affected by age whereas 172 proteins were differentially expressed by vessel type. Hierarchical clustering revealed that 207 proteins were significantly changed or clustered by age. Vitamin B6 pathway, Biosynthesis of antibiotics, Regulation of actin cytoskeleton and Endocytosis were the top enriched KEGG pathways by age. Several proteins in the RhoA/Rho-kinase pathway changed in a manner consistent with hypertension and dysregulation of cerebral perfusion. Although aging had a less profound effect than vessel type on the resistance artery proteome, regulation of actin cytoskeleton, including the RhoA/Rho-kinase pathway, is an important target for age-dependent hypertension., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Little is known on the cerebrovascular BDNF (brain-derived neurotrophic factor)/TrkB (tropomyosin related kinase B) pathway. This study investigated the contribution of endogenous endothelial BDNF to the control of vascular tone of rat middle cerebral artery (MCA) and the capacity of exogenous agonist of TrkB receptors to induce their relaxation. Endothelial cells constitutively expressed both BDNF and activated TrkB receptors. Supporting endothelial BDNF as an autocrine regulator of basal myogenic tone, incubation of MCA with the TrkB antagonist cyclotraxin B induced contraction as observed with incubation in the presence of inhibitors of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) production. Exposure of MCA with the TrkB agonist LM22A-4 that increased expression of TrkB receptors phosphorylated at tyrosine 816 induced relaxation of preconstricted MCA (EC 50 6.7 × 10 -8  mol/L) as efficiently than acetylcholine (EC 50 5.3 × 10 -8  mol/L). Finally, endothelium removal, exposure to a TrkB antagonist or to inhibitors of NO and EDHF production prevented the relaxant effect of LM22A-4. In conclusion, our study identified endothelial BDNF as a new autocrine regulator of vascular tone of MCA, thus making the endothelial BDNF/TrkB pathway an attractive target for strategies aiming to improve blood supply to the brain., (Copyright © 2021. Published by Elsevier Inc.)

Using detection markers in serum has the advantages of simplicity, repeatability and the capability. This study combined the use of serum glial fibrillary acidic protein (GFAP) and S100B protein (S100B) with imaging tools to confirm the role of serum biomarkers in evaluating the cerebral vessel reactivity after carotid artery stenting (CAS). After CAS, the serum concentrations of GFAP and S100B increased to the peak at 24 h after operation, and then gradually decreased. The mean flow velocity (MFV) (pre-operation, post-operation, 30 days follow-up: 47.65 ± 17.24 cm/s, 62.37 ± 18.25 cm/s, 70.29 ± 16.89 cm/s; P < 0.05) and pulsatility index (PI) (pre-operation, post-operation, 30 days follow-up: 0.78 ± 0.21, 0.98 ± 0.19, 1.02 ± 0.20; P < 0.05) increased significantly in the ipsilateral middle cerebral artery after CAS. At the 30-day follow-up, the cerebrovascular reserve (CVR) (post-operation, 30 days follow-up: 27.47 ± 12.13 cm/s, 31.92 ± 10.94 cm/s; P < 0.05) improved significantly. In patients with different degrees of stenosis, the more severe the stenosis in the carotid artery, the more obvious the improvement of CVR at the 30 days of follow-up (CVR changes: 11.08 ± 7.95 cm/s, Kendall's tau-b = 0.645, P < 0.001). And the serum concentrations of GFAP (r = - 0.629, P < 0.0001) and S100B (r = - 0.604, P < 0.0001) correlated negatively with CVR at 30 days after CAS. Therefore, we recommend using the biomarkers GFAP and S100B associated with imaging tools such as transcranial Doppler (TCD) and Magnetic resonance imaging (MRI) to evaluate the cerebral vessel reactivity following CAS., (© 2021. The Author(s).)

Objective: To investigate the predictive value of pre-induction digital examination, sonographic measurements and parity for the prediction of non-reassuring fetal status and cord arterial pH < 7.2 prior to the induction of labor (IOL)., Method: This was a prospective observational study, including 384 term pregnancies undergoing IOL. Before the IOL, the Bishop score (BS) by digital examination, sonographic Doppler parameters and the estimated fetal weight (EFW) was assessed. The fetal cord arterial was sampled to measure the pH at delivery. Multivariate logistic regression analysis was performed to identify independent predictors of non-reassuring fetal status and low cord arterial pH., Results: Forty four cases (11.5%) had non-reassuring fetal status, and 76 cases (19.8%) had fetal cord arterial pH < 7.2. In the non-reassuring fetal status group, the incidence of cord arterial pH < 7.2 was significantly higher than that in the normal fetal heart rate group (χ 2  = 6.401, p = 0.011). Multivariate analysis indicated that significant independent predictors of non-reassuring fetal status were nulliparity (adjusted odds ratio [AOR]: 3.746, p = 0.003), EFW < 10 th percentile (AOR: 3.764, p = 0.003) and cerebroplacental ratio (CPR) < 10 th centile (AOR:4.755, p < 0.001). In the prediction of non-reassuring fetal status, the performance of the combination of nulliparity and EFW < 10th percentile was improved by the addition of CPR < 10th percentile (AUC: 0.681, (95%CI: 0.636 to 0.742) vs 0.756, (95%CI:0.713 to 0.795)), but the difference was not significant (DeLong test: z = 1.039, p = 0.053).. None of the above variables were predictors of cord arterial pH < 7.2., Conclusion: The risk of fetal acidosis has increased in cases of non-reassuring fetal status. Nulliparity, small for gestational age and CPR < 10th centile are independent predictors for non-reassuring fetal status in term fetuses, though the addition of CPR < 10th centile could not significantly improve the screening accuracy.

We previously reported that deficiency in 20-HETE or CYP4A impaired the myogenic response and autoregulation of cerebral blood flow (CBF) in rats. The present study demonstrated that CYP4A was coexpressed with alpha-smooth muscle actin (α-SMA) in vascular smooth muscle cells (VSMCs) and most pericytes along parenchymal arteries (PAs) isolated from SD rats. Cell contractile capabilities of cerebral VSMCs and pericytes were reduced with a 20-HETE synthesis inhibitor, HET0016, but restored with 20-HETE analog WIT003. Similarly, intact myogenic responses of the middle cerebral artery and PA of SD rats decreased with HET0016 and were rescued by WIT003. The myogenic response of the PA was abolished in SS and was restored in SS.BN5 and SS.Cyp4a1 rats. HET0016 enhanced CBF and impaired its autoregulation in the surface and deep cortex of SD rats. These results demonstrate that 20-HETE has a direct effect on cerebral mural cell contractility that may play an essential role in controlling cerebral vascular function., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Preeclampsia affects 5-8% of pregnancies and is characterized by hypertension, placental ischemia, neurological impairment, and an increase in circulating inflammatory cytokines, including Interleukin-17 (IL17). While placental ischemia has also been shown to impair cerebrovascular function, it is not known which placental-associated factor(s) drive this effect. The purpose of this study was to examine the effects of IL17 on cerebrovascular function during pregnancy. To achieve this goal, pregnant rats were infused with either IL17 (150 pg/day, 5 days, osmotic minipump), or vehicle (saline/0.7% BSA osmotic minipump) starting at gestational day (GD) 14. On GD 19, the cerebral blood flow (CBF) response to increases in mean arterial pressure (MAP) was measured in vivo, and myogenic constrictor responses of the middle cerebral artery (MCA) were assessed ex vivo. IL17 increased MAP but impaired CBF responses only at the highest arterial pressure measured (190 mmHg). Myogenic constrictor responses overall were mostly unaffected by IL17 infusion; however, the intraluminal pressure at which peak myogenic tone was generated was lower in the IL17 infused group (120 vs 165 mm Hg), suggesting maximal tone is exerted at lower intraluminal pressures in IL17-treated pregnant rats. Consistent with the lack of substantial change in overall myogenic responsiveness, there was no difference in cerebral vessel expression of putative mechanosensitive protein βENaC, but a tendency towards a decrease in ASIC2 (p = 0.067) in IL17 rats. This study suggests that infusion of IL17 independent of other placental ischemia-associated factors is insufficient to recapitulate the features of impaired cerebrovascular function during placental ischemia. Further studies to examine of the role of other pro-inflammatory cytokines, individually or a combination, are necessary to determine mechanisms of cerebral vascular dysfunction during preeclampsia., (Copyright © 2021. Published by Elsevier B.V.)

This study aimed to determine the mechanosensing role of angiotensin II type 1 receptor (AT 1 R) in flow-induced dilation (FID) and oxidative stress production in middle cerebral arteries (MCA) of Sprague-Dawley rats. Eleven-week old, healthy male Sprague-Dawley rats on a standard diet were given the AT 1 R blocker losartan (1 mg/mL) in drinking water (losartan group) or tap water (control group) ad libitum for 7 days. Blockade of AT 1 R attenuated FID and acetylcholine-induced dilation was compared with control group. Nitric oxide (NO) synthase inhibitor N ω -nitro-l-arginine methyl ester (l-NAME) and cyclooxygenase inhibitor indomethacin (Indo) significantly reduced FID in control group. The attenuated FID in losartan group was further reduced by Indo only at Δ100 mmHg, whereas l-NAME had no effect. In losartan group, Tempol (a superoxide scavenger) restored dilatation, whereas Tempol + l-NAME together significantly reduced FID compared with restored dilatation with Tempol alone. Direct fluorescence measurements of NO and reactive oxygen species (ROS) production in MCA, in no-flow conditions revealed significantly reduced vascular NO levels with AT 1 R blockade compared with control group, whereas in flow condition increased the NO and ROS production in losartan group and had no effect in the control group. In losartan group, Tempol decreased ROS production in both no-flow and flow conditions. AT 1 R blockade elicited increased serum concentrations of ANG II, 8-iso-PGF2α, and TBARS, and decreased antioxidant enzyme activity (SOD and CAT). These results suggest that in small isolated cerebral arteries: 1 ) AT 1 receptor maintains dilations in physiological conditions; 2 ) AT 1 R blockade leads to increased vascular and systemic oxidative stress, which underlies impaired FID. NEW & NOTEWORTHY The AT 1 R blockade impaired the endothelium-dependent, both flow- and acetylcholine-induced dilations of MCA by decreasing vascular NO production and increasing the level of vascular and systemic oxidative stress, whereas it mildly influenced the vascular wall inflammatory phenotype, but had no effect on the systemic inflammatory response. Our data provide functional and molecular evidence for an important role of AT 1 receptor activation in physiological conditions, suggesting that AT 1 receptors have multiple biological functions.

The obese Zucker rat (OZR) manifests multiple risk factors for impaired cerebrovascular function, including hypertension and insulin resistance although how they combine to produce integrated vascular function is unclear. As studies have suggested that myogenic activation (MA) severity for middle cerebral arteries (MCAs) may be proportional to hypertension severity, we hypothesized that MA will negatively correlate with dilator reactivity in OZR. MA of MCA from OZR was divided into low, medium, and high based on the slope of MA, while MCA reactivity and vascular metabolite bioavailability were assessed in all groups. Endothelium-dependent dilation of MCA in OZR was attenuated and correlated with the MA slope. Treatment of OZR MCA with TEMPOL (antioxidant) improved dilation in low or medium MA groups, but had less impact on high MA. Alternatively, treatment with gadolinium to normalize MA in OZR had reduced impact on dilator reactivity in MCA from low and medium MA groups, but improved responses in the high group. Treatment with both agents resulted in dilator responses that were comparable across all groups. These results suggest that, under conditions with stronger MA, endothelial function may receive some protection despite the environment, potentially from the ability of MCA to reduce wall tension despite increased pressure., (© 2021 S. Karger AG, Basel.)

BACKGROUND The relative efficacy of carotid endarterectomy (CEA)/thromboendarterectomy (TEA) and carotid artery stenting (CAS) already has been compared in randomized controlled trials and a meta-analysis, but only limited data exist describing the status of cerebral metabolism before and after these interventions. The aim of the present study was to compare metabolic changes before and after treatment of carotid stenosis and assess their potential clinical implications.   MATERIAL AND METHODS Patients with asymptomatic unilateral critical internal CAS were imaged with proton 3T magnetic resonance spectroscopy (H-MRS) because the technique is more sensitive than regular magnetic resonance imaging for detection of the early signs of ischemic events. Abnormal metabolite ratios detected with H-MRS may precede actual morphological changes associated with hypoperfusion as well as reperfusion changes. Ipsilateral and contralateral middle cerebral artery vascular territories were both evaluated before and after vascular intervention. H-MRS was performed within 24 h before and after surgery. Correlations in the metabolic data from H-MRS for N-acetylaspartic acid (NAA)+N-acetylaspartylglutamate, creatinine (Cr)+phosphocreatinine, and phosphocholine+glycerophosphocholine (Cho) were sought. RESULTS H-MRS voxels from 11 subjects were analyzed. Values for dCho/CrI, dCho/CrC and Cho/Naal (P<0.001) were significantly higher ipsilaterally than contralaterally. Ratios for dNaa/ChoC and Cho/NaaC were significantly higher on the non-operated side (P<0.001). CONCLUSIONS H-MRS may be helpful for assessment of patients with CAS, particularly because unlike other modalities, it reveals postoperative changes in metabolic brain status. Initial results indicate the important role of perioperative neuroprotective treatment.

Prediabetes is a highly prevalent stage of early metabolic dysfunction that poses a high risk for cardiovascular and cognitive impairment without a clear pathological mechanism. Here, we used a non-obese prediabetic rat model previously developed in our laboratory to examine this mechanism. These rats were subjected to a mild metabolic challenge leading to hyperinsulinemia without hyperglycemia or obesity. This was associated with impaired hippocampal-dependent cognitive functions together with an augmented cerebrovascular myogenic tone. Consequently, hippocampal expression of hypoxia-inducible factor-1α increased, together with markers of mitochondrial dysfunction and oxidative stress. In parallel, the phosphorylation of Akt and mTOR increased in the prediabetic rat hippocampus alongside increased expression of p62 and LC3 puncta indicating a possible repression of autophagic flux. Neuroinflammation and neuronal apoptosis were detected in the hippocampal CA1 area as increased CD68 and IBA-1 staining, as well as increased TUNEL staining and caspase-3 activity, respectively. Treatment with metformin or pioglitazone, at a previously determined vasculoprotective non-hypoglycemic dose, reversed the cerebrovascular and hippocampal molecular alterations and ameliorated cognitive function. The present study proposes a mechanistic framework whereby prediabetic cerebrovascular impairment potentially leads to a mild hypoxic state that is exacerbated by the metabolic dysfunction-driven suppression of neuronal autophagy leading to cognitive impairment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Stroke-induced changes in neuroglia determine the basic conditions for the survival and damage of neurons in the ischemic core. Here, we studied the immunolocalization of glial cell line-derived neurotrophic factor (GDNF), glial fibrillary acidic protein (GFAP), ionized calcium-binding adaptor molecule 1 (Iba-1), and S-100β in the rat parietal cortex after constant occlusion of the middle cerebral artery. These cytoplasmic proteins are specific for different glial cell types. They are used as indicators of activated microglia and astrocytes in immunocytochemical studies. The distribution pattern of all markers changed dramatically with time. GFAP- and S-100β-positive astrocytes were observed in the penumbra zone and marked its boundaries. In days 1-8 after surgery, in the ischemic core, the number of S-100β-immunoreactive astrocytes decreased, and individual pyramidal cells appeared. S-100β-expressing pyramidal cells were localized in cortical layers III and V. They were only found in the ischemic core. Their proportion to the total number of cells was 37.3 ± 3.9 %, 22.2 ± 1.2 %, 16.3 ± 2.3 %, and 5.4 ± 0.3 % on days 1, 3, 8, and 14 after surgery. On day 21, no S-100β-expressing pyramidal cells were observed. The spatial density of GFAP- and S-100β-positive astrocytes increased in the penumbra region adjacent to the ischemic core and decreased in the penumbral periphery. As a result, the width of the perifocal penumbra zone decreased substantially at later stages of the stroke. In the penumbra, on days 1-3 after ischemic injury, GDNF immunoreactivity was mainly localized in neurons, while later on (days 8-21) it was mainly constrained to astrocyte glia. In intact rats, GDNF-positive neurons were situated in cortical layers II/III and V/VI and made up 52 ± 4.5 % of the total neuron population. Their proportion to the total number of neurons was 29 ± 2.1 %, 13.8 ± 0.6 %, and 3.1 ± 0.2 % on days 1, 8, and 21 after surgery. The number of GDNF-positive astrocytes, on the opposite, increased with time after ischemic injury. Iba-1-reactive microglia was mainly localized to the ischemic core. Microglial cells appeared activated as evidenced by their increased size and decreased number of processes and branching density. The spatial density of microglia reached a peak ​​on day 8 after ischemic injury both in the ischemic core and penumbra. An increase in the number of Iba-1-reactive microglia in the ischemic core correlated with a decrease of the number of GFAP-positive astrocytes. The results are discussed in the context of participation of neuroglia in regulation of various neuroprotective and destructive processes., Competing Interests: Declaration of Competing Interest The authors have no competing interests., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Pressure-induced constriction (PIC) is an inherent response of small arteries and arterioles in which increases in intraluminal pressure evoke vasoconstriction. It is a critical mechanism of blood flow autoregulation in the kidney and brain. Degenerin (Deg) and transient receptor potential (Trp) protein families have been implicated in transduction of PIC because of evolutionary links to mechanosensing in the nematode and fly. While TrpC6 has been suggested to contribute to PIC signaling, direct supporting evidence is contradictory. Therefore, the aim of this study was to determine the importance of TrpC6 in PIC signaling using a mouse model lacking TrpC6. To address this aim, we evaluated graded pressure (20-90 mmHg), depolarization (4-80 mM KCl)-, and adrenergic receptor (phenylephrine; PE 10 -7 -10 -4 M)-mediated constriction of isolated middle cerebral artery (MCA) segments from 9-wk-old male wild-type (TrpC6 +/+ , n = 7) and homozygous null (TrpC6 -/- , n = 9) TrpC6 mice (Jackson Laboratories). Isolated MCA segments were cannulated and pressurized with physiological salt solution using pressure myography (Living Systems). Vasoconstrictor responses to KCl and PE were identical in TrpC6 -/- and TrpC6 +/+ mice. In contrast, PIC responses were totally abolished in TrpC6 -/- mice. At 90 mmHg, the calculated myogenic tone was -0.8 ± 0.5 vs. 10.7 ± 1.7%, P = 0.0002 in TrpC6 -/- and TrpC6 +/+ mice, respectively. Additionally, there were no changes in mechanical properties of circumferential wall strain and stress or morphological properties of wall thickness and wall-to-lumen ratio at 50 mmHg between TrpPC6 -/- and TrpC6 +/+ mice. Although these results demonstrate that TrpC6 is critical for the integrated PIC response, they do not identify whether TrpC6 acts as a mechanosensor or a downstream signaling component. NEW & NOTEWORTHY Pressure-induced, but not agonist-induced, vasoconstriction is abolished in the middle cerebral artery (MCA) of TrpC6 null mice. TrpC6 localization in dissociated cerebral vascular smooth muscle cells is primarily cytoplasmic and not associated with the surface membrane where a mechanoelectrical coupler might be expected. These findings suggest that TrpC6 is required for transduction of pressure-induced constriction in the MCA; however, its role as a mechanoelectrical coupler or downstream signal amplifier remains unresolved.

Aims: The myogenic reactivity of the middle cerebral arteries (MCA) protects the brain by altering the diameter in response to changes in lumen pressure. Large conductance potassium (BK) channels are known to regulate the myogenic reactivity, yet, it is not clear how aging alters the myogenic reactivity via the BK channel in males and females. Thus, we hypothesize that age-associated changes in BK channel subunits modulate the myogenic reactivity in a sex-specific manner., Methods and Results: We used vascular reactivity, patch-clamp, and biochemical methods to measure myogenic reactivity, BK channel function, and expression, respectively in cerebral vessels of adult and aged male and female Sprague Dawley rats. Our results suggest that aging and ovariectomy (OVX) exaggerated the myogenic reactivity of MCA in females but attenuated it in males. Aging induced outward eutrophic remodelling in females but inward hypertrophic remodelling in males. Aging decreased total, Kv, BK channel currents, and spontaneous transient outward currents (STOC) in vascular smooth muscle cells isolated from females, but not in males. Aging increased BKα subunit mRNA and protein both in males and females. However, aging decreased BKβ1 subunit protein and mRNA in females only. In males, BKβ1 mRNA is increased, but protein is decreased. Iberiotoxin-induced MCA constriction is lower in aged females but higher in aged males. Activation of BKα (10 µM NS1619) and BKβ1 (10 µM S-Equol) subunits failed to increase STOCs and were unable to decrease the myogenic reactivity of MCA in aged female but not in aged male rats. OVX decreased, but chronic supplementation of oestradiol restored BK channel expression and function., Conclusion: Overall our results suggest that aging or OVX-associated downregulation of the BKβ1 expression and function in females results in exaggerated myogenic reactivity of MCA. However, age-associated increase in BK channel function in males attenuated myogenic reactivity of MCA., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Hyponatraemia, a water-electrolyte disorder diagnosed in patients with subarachnoid haemorrhage (SAH), increases a risk of persistent vasospasm. In majority of cases, hyponatraemia results from inappropriate secretion of vasopressin (AVP). The effect of AVP-associated hyponatraemia on cerebral vasculature is unknown. The present study aimed to elucidate the role of AVP in the response of the middle cerebral artery (MCA) of the rat to hyponatraemia. Isolated, cannulated, and pressurized rat MCAs were perfused/superfused with physiological (Na +  = 144 mmol/L) buffer or low-sodium (Na +  = 121 mmol/L) buffer containing either AVP or angiotensin II (ANG II). ANG II was used to check if the effect of low plasma sodium concentration combined with AVP on the MCA tone is unique to vasopressin. At physiological Na + concentration, vasopressin (1.4 × 10 -11  mol/L) or angiotensin II (10 -9  mol/L) resulted in relaxation of the MCA. Substitution of low-sodium for the normal sodium buffer with the same concentration of AVP, resulted in the constriction of the MCA. This effect was absent after removal of the endothelium, administration of vasopressin V 1 receptor antagonist or concomitant inhibition of endothelin-1 receptors and synthesis of thromboxane A 2. In contrast, no constriction of the MCA in low-sodium buffer was observed when AVP was replaced with ANG II. Our data suggest that presence of vasopressin and low sodium ion concentration results in the change of endothelium phenotype from pro-vasodilatory to pro-vasoconstrictory. This phenomenon may be an overlooked factor contributing to vasospasm in SAH patients with hyponatraemia caused by inappropriate antidiuretic hormone secretion (SIADH)., (© 2019 John Wiley & Sons Australia, Ltd.)

Since 2009, we built up a database which presently includes more than 2000 electrohypersensitivity (EHS) and/or multiple chemical sensitivity (MCS) self-reported cases. This database shows that EHS is associated in 30% of the cases with MCS, and that MCS precedes the occurrence of EHS in 37% of these EHS/MCS-associated cases. EHS and MCS can be characterized clinically by a similar symptomatic picture, and biologically by low-grade inflammation and an autoimmune response involving autoantibodies against O-myelin. Moreover, 80% of the patients with EHS present with one, two, or three detectable oxidative stress biomarkers in their peripheral blood, meaning that overall these patients present with a true objective somatic disorder. Moreover, by using ultrasonic cerebral tomosphygmography and transcranial Doppler ultrasonography, we showed that cases have a defect in the middle cerebral artery hemodynamics, and we localized a tissue pulsometric index deficiency in the capsulo-thalamic area of the temporal lobes, suggesting the involvement of the limbic system and the thalamus. Altogether, these data strongly suggest that EHS is a neurologic pathological disorder which can be diagnosed, treated, and prevented. Because EHS is becoming a new insidious worldwide plague involving millions of people, we ask the World Health Organization (WHO) to include EHS as a neurologic disorder in the international classification of diseases.

Background: Patients with pulmonary arterial hypertension (PAH) have lower cerebral blood flow (CBF) and oxygenation compared to healthy sedentary subjects, the latter negatively correlating with exercise capacity during incremental cycling exercise. We hypothesized that patients would also exhibit altered CBF and oxygenation during endurance exercise, which would correlate with endurance time., Methods: Resting and exercise cardiorespiratory parameters, blood velocity in the middle cerebral artery (MCAv; transcranial doppler) and cerebral oxygenation (relative changes in cerebral tissue oxygenation index (ΔcTOI) and cerebral deoxyhemoglobin (ΔcHHb); near-infrared spectroscopy) were continuously monitored in nine PAH patients and 10 healthy-matched controls throughout endurance exercise. Cardiac output (CO), systemic blood pressure (BP) and oxygen saturation (SpO 2 ), ventilatory metrics and end-tidal CO 2 pressure (P ET CO 2 ) were also assessed noninvasively., Results: Despite a lower workload and endurance oxygen consumption, similar CO and systemic BP, ΔcTOI was lower in PAH patients compared to controls (p < .01 for interaction). As expected during exercise, patients were characterized by an altered MCAv response to exercise, a lower P ET CO 2 and SpO 2 , as wells as a higher minute-ventilation/CO 2 production ratio ( V ˙ E / V ˙ CO 2 ratio). An uncoupling between changes in MCAv and P ET CO 2 during the cycling endurance exercise was also progressively apparent in PAH patients, but absent in healthy controls. Both cHHb and ΔcTOI correlated with V ˙ E / V ˙ CO 2 ratio (r = 0.50 and r = -0.52; both p < .05 respectively), but not with endurance time., Conclusion: PAH patients present an abnormal cerebrovascular profile during endurance exercise with a lower cerebral oxygenation that correlate with hyperventilation but not endurance exercise time. These findings complement the physiological characterization of the cerebral vascular responses to exercise in PAH patients., (© 2020 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Purpose: Intracranial plaque gadolinium enhancement revealed by high-resolution MRI imaging (HR MRI) is considered as a marker of plaque inflammation, a contributing factor of plaque unstability. The aim of the present study was to assess the distribution of gadolinium enhancement in intracranial atherosclerosis., Methods: Single center analysis of ischemic stroke patients with intracranial atherosclerotic stenosis of M1 or M2 segments of middle cerebral artery, or terminal internal carotid artery (ICA) based on CT-angio or MR-angio. High-resolution MRI imaging (HRMRI) was performed within 6 first weeks following the index event, with 3DT2 BB (black-blood) and 3D T1 BB MR sequences pre and post-contrast administration., Results: We identified 8 patients with 14 plaques, 4 were deemed non-culprit and 10 culprit. All culprit plaques (10/10 plaques) and 3 out of 4 non-culprit plaques showed a gadolinium enhancement., Conclusion: At the acute/subacute stage of stroke, a gadolinium enhancement may affect multiple asymptomatic intracranial plaques and may reflect a global inflammatory state., (Copyright © 2019. Published by Elsevier Masson SAS.)

Objective: Cerebral arterial networks match blood flow delivery with neural activity. Neurovascular response begins with a stimulus and a focal change in vessel diameter, which by themselves is inconsequential to blood flow magnitude, until they spread and alter the contractile status of neighboring arterial segments. We sought to define the mechanisms underlying integrated vascular behavior and considered the role of intercellular electrical signaling in this phenomenon. Approach and Results: Electron microscopic and histochemical analysis revealed the structural coupling of cerebrovascular cells and the expression of gap junctional subunits at the cell interfaces, enabling intercellular signaling among vascular cells. Indeed, robust vasomotor conduction was detected in human and mice cerebral arteries after focal vessel stimulation: a response attributed to endothelial gap junctional communication, as its genetic alteration attenuated this behavior. Conducted responses were observed to ascend from the penetrating arterioles, influencing the contractile status of cortical surface vessels, in a simulated model of cerebral arterial network. Ascending responses recognized in vivo after whisker stimulation were significantly attenuated in mice with altered endothelial gap junctional signaling confirming that gap junctional communication drives integrated vessel responses. The diminishment in vascular communication also impaired the critical ability of the cerebral vasculature to maintain blood flow homeostasis and hence tissue viability after stroke., Conclusions: Our findings highlight the integral role of intercellular electrical signaling in transcribing focal stimuli into coordinated changes in cerebrovascular contractile activity and expose, a hitherto unknown mechanism for flow regulation after stroke.

Emerging data revealed that rheumatoid arthritis (RA) is associated with higher risk of cerebrovascular diseases. Whereas cerebral endothelial dysfunction is acknowledged as a critical aspect of cerebrovascular diseases, its presence in RA and the mechanisms involved are currently unknown. By using the model of rat adjuvant-induced arthritis (AIA), the present study investigated cerebrovascular reactivity in pressurized middle cerebral arteries (MCA) on day 33 post-immunization. The results revealed that arthritis induced a dramatic decrease in the vasodilatory response to acetylcholine (ACh), ADP, and bradykinin (n = 7-9 arteries, p < 0.0001). By using nor-NOHA, L-NAME, BH 4 , and Tempol, the results showed that the reduced response to ACh relied on arginase overactivation (n = 8), low NOS activity (n = 8), BH 4 deficiency (n = 9), and excessive superoxide production (n = 9). Immunohistological analysis revealed an endothelial upregulation of arginase 2 (p < 0.05, n = 5-6) and NADPH oxidase (p < 0.05, n = 5-7) while eNOS expression was unchanged in AIA (n = 6). To assess whether arginase inhibition may be a relevant therapeutic, AIA rats were treated with an arginase inhibitor (nor-NOHA, 40 mg/kg/day, i.p., n = 20 rats) daily from day 10 to day 33 post-immunization. The treatment alleviated the impaired response of MCA to endothelium-dependent agonists, through an increase in NOS signaling and a suppression of BH 4 deficiency and superoxide overproduction. By contrast, it did not change the course of arthritis. In conclusion, arthritis induced a cerebrovascular endothelial dysfunction involving an imbalance in the arginase/NOS pathway. Arginase inhibition appears as a promising therapy beyond anti-rheumatic drugs for reducing the risk of cerebrovascular diseases in RA.

Inflammatory response participates in the overall pathophysiological process of stroke. It is a promising strategy to develop antistroke drugs targeting inflammation. This study is aimed at investigating the therapeutic effect and anti-inflammatory mechanism of salvianolic acid D (SalD) against cerebral ischemia/reperfusion (I/R) injury. A rat middle cerebral artery occlusion/reperfusion (MCAO/R) injury model was established, and an oxygen-glucose deprivation/reoxygenation (OGD/R) injury model was established in PC12 cells. Neurological deficit score, cerebral infarction, and edema were studied in vivo . Cell viability was achieved using the MTT method in vitro . The Bax, Bcl-2, cytochrome c, HMGB1, TLR4, TRAF6, NF- κ B p65, p-NF- κ B p65, and cleaved caspase-3 and -9 were tested via the Western blot method. Cytokines and cytokine mRNA, including TNF- α , IL-1 β , and IL-6, were studied via ELISA and PCR methods. The translocation of HMGB1 and NF- κ B were studied by immunofluorescence assay. The HMGB1/NeuN, HMGB1/GFAP, and HMGB1/Iba1 double staining was carried out to observe the localization of HMGB1 in different cells. Results showed that SalD alleviated neurological impairment, decreased cerebral infarction, and reduced edema in I/R rats. SalD improved OGD/R-downregulated PC12 cell viability. SalD also promoted Bcl-2 expression and suppressed Bax, cytochrome c, and cleaved caspase-3 and -9 expression. SalD decreased the intensity of TLR4, MyD88, and TRAF6 proteins both in vivo and in vitro , and significantly inhibited the NF- κ B nuclear translocation induced by I/R and OGD/R. What's more, SalD inhibited HMGB1 cytoplasmic translocation in neurons, astrocytes, and microglia in both the cortex and hippocampus regions of I/R rats. In conclusion, SalD can alleviate I/R-induced cerebral injury in rats and increase the PC12 cell viability affected by OGD/R. The anti-inflammatory mechanism of SalD might result from the decreased nuclear-to-cytoplasmic translocation of HMGB1 and the inhibition on its downstream TLR4/MyD88/NF- κ B signaling., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 Wen Zhang et al.)

Subarachnoid hemorrhage (SAH) is a type of hemorrhagic stroke with a high short-term mortality rate which leads to cognitive impairments that reduce the quality of life of the majority of patients. The miRNA-143/145 cluster is highly expressed in vascular smooth muscle cells (VSMC) and has been shown to be necessary for differentiation and function, as well as an important determinant for phenotypic modulation/switching of VSMCs in response to vascular injury. We aimed to determine whether miRNA-143 and miRNA-145 are important regulators of phenotypical changes of VSMCs in relation to SAH, as well as establishing their physiological role in the cerebral vasculature. We applied quantitative PCR to study ischemia-induced alterations in the expression of miRNA-143 and miRNA-145, for rat cerebral vasculature, in an ex vivo organ culture model and an in vivo SAH model. To determine the physiological importance, we did myograph studies on basilar and femoral arteries from miRNA-143/145 knockout mice. miRNA-143 and miRNA-145 are not upregulated in the vasculature following our SAH model, despite the upregulation of miR-145 in the organ culture model. Regarding physiological function, miRNA-143 and miRNA-145 are very important for general contractility in cerebral vessels in response to depolarization, angiotensin II, and endothelin-1. Applying an anti-miRNA targeting approach in SAH does not seem to be a feasible approach because miRNA-143 and miRNA-145 are not upregulated following SAH. The knockout mouse data suggest that targeting miRNA-143 and miRNA-145 would lead to a general reduced contractility of the cerebral vasculature and unwanted dedifferentiation of VSMCs.

New Findings: What is the central question of the study? What are the effects of acute mental stress on the mechanisms regulating cerebral blood flow? What is the main finding and its importance? The major new findings are as follows: (i) high mental stress and hypercapnia had an interactive effect on mean middle cerebral artery blood velocity; (ii) high mental stress altered the regulation of cerebral blood flow; (iii) the increased cerebrovascular hypercapnic reactivity was not driven by changes in mean arterial pressure alone; and (iv) this increased perfusion with mental stress appeared not to be justified functionally by an increase in oxygen demand (as determined by near-infrared spectroscopy-derived measures)., Abstract: In this study, we examined the effects of acute mental stress on cerebrovascular function. Sixteen participants (aged 23 ± 4 years; five female) were exposed to low and high mental stress using simple arithmetic (counting backwards from 1000) and more complex arithmetic (serial subtraction of 13 from a rapidly changing four-digit number), respectively. During consecutive conditions of baseline, low stress and high stress, end-tidal partial pressure of CO 2 ( P ET , C O 2 ) was recorded at normocapnia (37 ± 3 mmHg) and clamped at two elevated levels (P < 0.01): 41 ± 1 and 46 ± 1 mmHg. Mean right middle cerebral artery blood velocity (MCAv mean ; transcranial Doppler ultrasound), right prefrontal cortex haemodynamics (near-infrared spectroscopy) and mean arterial blood pressure (MAP; finger photoplethysmography) were measured continuously. Cerebrovascular hypercapnic reactivity (ΔMCAv mean /Δ P ET , C O 2 ), cerebrovascular conductance (CVC; MCAv mean /MAP), CVC CO 2 reactivity (ΔCVC/Δ P ET , C O 2 ) and total peripheral resistance (MAP/cardiac output) were calculated. Acute high mental stress increased MCAv mean by 7 ± 7%, and more so at higher P ET , C O 2 (32 ± 10%; interaction, P = 0.03), illustrating increased sensitivity to CO 2 (i.e. its major regulator). High mental stress also increased MAP (17 ± 9%; P ≤ 0.01), coinciding with increased near-infrared spectroscopy-derived prefrontal haemoglobin volume and saturation measures. High mental stress elevated both cerebrovascular hypercapnic and conductance reactivities (main effect of stress, P ≤ 0.04). These findings indicate that the cerebrovascular response to acute high mental stress results in a coordinated regulation between multiple processes., (© 2019 The Authors. Experimental Physiology © 2019 The Physiological Society.)

A 70-year-old woman had spontaneous resolution of an embolism in her right middle cerebral artery (MCA) (day 1); another embolism occurred in her left MCA (day 3), which was promptly removed. On day 5, F-FDG PET/CT performed for staging mediastinal lymphoma showed marked FDG accumulation in the left MCA territory, whereas a defect was seen in the right insular region. Eventually, bilateral lesions developed irreversible infarction. Anaerobic metabolism and/or inflammation in acute-phase infarction were the supposed mechanism for the increased accumulation of FDG in her left MCA territory.

Hypothesis: This study tested the hypothesis that dietary activation of the master antioxidant and cell protective transcription factor nuclear factor, erythroid -2-like 2 (NRF2), protects against salt-induced vascular dysfunction by restoring redox homeostasis in the vasculature., Methods: Male Sprague-Dawley rats and Syrian hamsters were fed a HS (4.0% NaCl) diet containing ~60 mg/kg/day Protandim supplement for 2 weeks and compared to controls fed HS diet alone., Results: Protandim supplementation restoredendothelium-dependent vasodilation in response to acetylcholine (ACh) in middle cerebral arteries (MCA)of HS-fed rats and hamster cheek pouch arterioles, and increased microvessel density in the cremastermuscle of HS-fed rats. The restored dilation to ACh in MCA of Protandim-treated rats was prevented by inhibiting nitric oxide synthase (NOS) with L-NAME [100 μM] and was absent in MCA from Nrf2 (-/-) knockout rats fed HS diet. Basilar arteries from HS-fed rats treated with Protandim exhibited significantly lower staining for mitochondrial oxidizing species than untreated animals fed HS diet alone; and Protandim treatment increased MnSOD (SOD2) protein expression in mesenteric arteries of HS-fed rats., Conclusions: These results suggest that dietary activation of NRF2 protects against salt-induced vascular dysfunction, vascular oxidative stress, and microvascular rarefaction by upregulating antioxidant defenses and reducing mitochondrial ROS levels., (© 2019 John Wiley & Sons Ltd.)

Objectives: To determine whether acupuncture at GB34 affects cerebral blood flow (CBF) via the anterior cerebral arteries (ACAs) and middle cerebral arteries (MCAs)., Methods: This study included 10 healthy young male volunteers. CBF velocity and cerebrovascular reactivity (CVR) were measured using transcranial Doppler sonography (TCD). The changes in hyperventilation-induced carbon dioxide (CO 2 ) reactivity and modified blood flow velocity at 40 mm Hg (CV40) were observed for both ACAs and MCAs before and after GB34 acupuncture treatment. Blood pressure and heart rate were also measured before and after GB34 acupuncture treatment., Results: The CO 2 reactivity of the ipsilateral MCA significantly increased after GB34 acupuncture treatment, compared with that at baseline (P=0.007). In contrast, the CO 2 reactivity of both ACAs and the contralateral MCA remained unchanged. The CV40 of both ACAs and MCAs did not change after GB34 acupuncture treatment and neither did the mean arterial blood pressure and heart rate., Conclusions: GB34 acupuncture treatment increased CO 2 reactivity specifically in the ipsilateral MCA, but had no effect on either the ACAs or the contralateral MCA. These data suggest that GB34 acupuncture treatment improves the vasodilatory potential of the cerebral vasculature to compensate for fluctuations caused by changes in external conditions and could potentially be useful for the treatment of disorders of the ipsilateral MCA circulation.

New Findings: What is the central question of this study? There is an interaction between the regulatory systems of respiration and cerebral blood flow, because the mediator (CO 2 ) is the same for both physiological systems. We examined whether the traditional method for determining cerebrovascular reactivity to CO 2 is modified by changes in respiration. What is the main finding and its importance? Cerebrovascular reactivity was modified by voluntary changes in respiration during hypercapnia. This finding suggests that an alteration in the respiratory system may result in under- or overestimation of cerebrovascular reactivity determined by traditional methods in healthy adults., Abstract: The cerebral vasculature is sensitive to changes in the arterial partial pressure of CO 2 . This physiological mechanism has been well established as a cerebrovascular reactivity to CO 2 (CVR). However, arterial CO 2 may not be an independent variable in the traditional method for assessment of CVR, because the cerebral blood flow response is also affected by the activation of respiratory drive or higher centres in the brain. We hypothesized that CVR is modified by changes in respiration. To test our hypothesis, in the present study, 10 young, healthy subjects performed hyper- or hypoventilation to change end-tidal CO 2 ( P ET , C O 2 ) with different concentrations of CO 2 in the inhaled gas (0, 2.0 and 3.5%). We measured middle cerebral artery mean blood flow velocity by transcranial Doppler ultrasonography to identify the cerebral blood flow response to change in P ET , C O 2 during each set of conditions. In each set of conditions, P ET , C O 2 was significantly altered by changes in ventilation, and middle cerebral artery mean blood flow velocity changed accordingly. However, the relationship between changes in middle cerebral artery mean blood flow velocity and P ET , C O 2 as a response curve of CVR was reset upwards and downwards by hypo- and hyperventilation, respectively, compared with CVR during normal ventilation. The findings of the present study suggest the possibility that an alteration in respiration might lead to under- or overestimation of CVR determined by the traditional methods., (© 2019 The Authors. Experimental Physiology © 2019 The Physiological Society.)

Familial hemiplegic migraine type 2 (FHM2) is associated with inherited point-mutations in the Na,K-ATPase α2 isoform, including G301R mutation. We hypothesized that this mutation affects specific aspects of vascular function, and thus compared cerebral and systemic arteries from heterozygote mice bearing the G301R mutation (Atp1a2 +/-G301R ) with wild type (WT). Middle cerebral (MCA) and mesenteric small artery (MSA) function was compared in an isometric myograph. Cerebral blood flow was assessed with Laser speckle analysis. Intracellular Ca 2+ and membrane potential were measured simultaneously. Protein expression was semi-quantified by immunohistochemistry. Protein phosphorylation was analysed by Western blot. MSA from Atp1a2 +/-G301R and WT showed similar contractile responses. The Atp1a2 +/-G301R MCA constricted stronger to U46619, endothelin and potassium compared to WT. This was associated with an increased depolarization, although the Ca 2+ change was smaller than in WT. The enhanced constriction of Atp1a2 +/-G301R MCA was associated with increased cSrc activation, stronger sensitization to [Ca 2+ ] i and increased MYPT1 phosphorylation. These differences were abolished by cSrc inhibition. Atp1a2 +/-G301R mice had reduced resting blood flow through MCA in comparison with WT mice . FHM2-associated mutation leads to elevated contractility of MCA due to sensitization of the contractile machinery to Ca 2+ , which is mediated via Na,K-ATPase/Src-kinase/MYPT1 signalling.

We previously reported that cerebral blood flow (CBF) was reduced by even mild +Gz hypergravity. Regional cerebral oxygen saturation as measured by near-infrared spectroscopy (C-rSO 2 ) has been widely used to detect cerebral ischemia in clinical practice. For example, decreases in C-rSO 2 reflect reduced CBF or arterial oxygen saturation. Thus it was hypothesized that C-rSO 2 would decrease in association with reduced CBF during mild hypergravity. To test this hypothesis, we measured CBF velocity by transcranial Doppler ultrasonography and C-rSO 2 during mild +Gz hypergravity while participants were in a sitting position. Among 17 male participants, 15 completed 21 min of exposure to +1.5 Gz generated by short-arm centrifuge. C-rSO 2 and mean CBF velocity in the middle cerebral artery (MCBFV MCA ) during centrifugation were averaged every 5 min and compared with pre-hypergravity (+1.0 Gz). C-rSO 2 did not change significantly throughout centrifugation, although MCBFV MCA gradually decreased from the beginning (-1.2% at 0-5 min), and significantly decreased at 5-10 min (-4.8%), 10-15 min (-6.7%), and 15-20 min (-7.4%). Contrary to our hypothesis, decreases in C-rSO 2 were not detected, despite reductions in CBF velocity during hypergravity. Since some assumptions, such as unaltered arteriovenous volume ratio, hemoglobin concentration, extracranial blood flow, and brain activity, need to be satisfied to monitor cerebral ischemia by C-rSO 2 , the present results suggest that these necessary assumptions for near-infrared spectroscopy are not always applicable, and that cerebral oxygenation may not precisely reflect decreases in CBF under mild +Gz hypergravity. NEW & NOTEWORTHY To our knowledge, this is the first study to evaluate simultaneously cerebral oxygenation monitored by near-infrared spectroscopy and cerebral blood flow (CBF) monitored by transcranial Doppler under +1.5 Gz hypergravity. Contrary to our hypothesis, there was no significant correlation between CBF velocity and regional cerebral oxygen saturation (C-rSO 2 ). However, an incomplete case nearly involving syncope suggests the possibility that C-rSO 2 can detect a remarkable decrease in CBF with development of presyncope during +Gz hypergravity.

Aims: The recent identification of acid sensing ion channels (ASICs) in vascular beds suggests their possible involvement in modulating vasomotor tone. Therefore, we investigated the gene expression profiles of ASIC subtypes in the middle cerebral artery (MCA) of Wistar rats and the functional implication of ASICs in acidosis-induced relaxation as well as maintenance of resting tension., Main Methods: Real time PCR was employed to study the pattern of ASIC mRNA expression in the MCA wall in comparison with (i) matching brain tissue samples and (ii) arteries cultured for 24 h and 48 h. The functional implication regarding vasomotor response to acidosis and maintenance of resting tension was assessed using in vitro myography., Key Findings: A robust mRNA expression of ASIC-1, -2 and -4 was found in brain tissue samples and to a lower extent in freshly isolated MCA. In the MCA wall, short term culture induced a down-regulation of ASIC-1 and -2 expression without any remarkable change in ASIC-4 expression. Acidosis induced a pH-related relaxation of freshly isolated MCA ring segments, being more pronounced after short term culture. Incubation with the ASIC blocker amiloride moderately enhanced acidosis-induced relaxation, in cultured MCAs somewhat stronger than in freshly isolated vessels. In addition, amiloride resulted in a decrease of resting tension, albeit only in freshly isolated MCA., Significance: Our results comprehensively describe ASIC subtype composition in the rat MCA in physiological and pathological conditions and strongly suggest the involvement of ASICs in the modulation of vasomotor responses under conditions of normal or decreased pH values., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Breath-hold divers (BHD) experience repeated bouts of severe hypoxia and hypercapnia with large increases in blood pressure. However, the impact of long-term breath-hold diving on cerebrovascular control remains poorly understood. The ability of cerebral blood vessels to respond rapidly to changes in blood pressure represents the property of dynamic autoregulation. The current investigation tested the hypothesis that breath-hold diving impairs dynamic autoregulation to a transient hypotensive stimulus. Seventeen BHD (3 women, 11 ± 9 yr of diving) and 15 healthy controls (2 women) completed two or three repeated sit-to-stand trials during spontaneous breathing and poikilocapnic conditions. Heart rate (HR), finger arterial blood pressure (BP), and cerebral blood flow velocity (BFV) from the right middle cerebral artery were measured continuously with three-lead electrocardiography, finger photoplethysmography, and transcranial Doppler ultrasonography, respectively. End-tidal carbon dioxide partial pressure was measured with a gas analyzer. Offline, an index of cerebrovascular resistance (CVRi) was calculated as the quotient of mean BP and BFV. The rate of the drop in CVRi relative to the change in BP provided the rate of regulation [RoR; (∆CVRi/∆T)/∆BP]. The BHD demonstrated slower RoR than controls ( P ≤ 0.001, d =  1.4). Underlying the reduced RoR in BHD was a longer time to reach nadir CVRi compared with controls ( P = 0.004, d  = 1.1). In concert with the longer CVRi response, the time to reach peak BFV following standing was longer in BHD than controls ( P = 0.01, d  = 0.9). The data suggest impaired dynamic autoregulatory mechanisms to hypotension in BHD. NEW & NOTEWORTHY Impairments in dynamic cerebral autoregulation to hypotension are associated with breath-hold diving. Although weakened autoregulation was observed acutely in this group during apneic stress, we are the first to report on chronic adaptations in cerebral autoregulation. Impaired vasomotor responses underlie the reduced rate of regulation, wherein breath-hold divers demonstrate a prolonged dilatory response to transient hypotension. The slower cerebral vasodilation produces a longer perturbation in cerebral blood flow velocity, increasing the risk of cerebral ischemia.

The diagnosis and management of fetal anemia has been at the forefront of advances in the fields of fetal physiology, immunology, fetal imaging, and fetal therapy among others. Alloimmunization and parvovirus infection are the leading cause of fetal anemia in the United States. The middle cerebral artery peak systolic velocity (MCA-PSV) diagnoses fetal anemia. Its discovery is considered one of the most important achievements in fetal medicine. Accumulation of experience in recent years as well as refinement of surgical techniques have led to safer invasive procedures. It is expected that long term follow-up of affected pregnancies, continues to reflect all these improvements in care. It is also expected that treatment of other less common causes of fetal anemia becomes more frequently reported and that the management principles of fetal anemia are successfully applied to other fetal pathologies.

Objective- Circulating complement factors are activated by tissue damage and contribute to acute brain injury. The deposition of MBL (mannose-binding lectin), one of the initiators of the lectin complement pathway, on the cerebral endothelium activated by ischemia is a major pathogenic event leading to brain injury. The molecular mechanisms through which MBL influences outcome after ischemia are not understood yet. Approach and Results- Here we show that MBL-deficient (MBL -/- ) mice subjected to cerebral ischemia display better flow recovery and less plasma extravasation in the brain than wild-type mice, as assessed by in vivo 2-photon microscopy. This results in reduced vascular dysfunction as shown by the shift from a pro- to an anti-inflammatory vascular phenotype associated with MBL deficiency. We also show that platelets directly bind MBL and that platelets from MBL -/- mice have reduced inflammatory phenotype as indicated by reduced IL-1α (interleukin-1α) content, as early as 6 hours after ischemia. Cultured human brain endothelial cells subjected to oxygen-glucose deprivation and exposed to platelets from MBL -/- mice present less cell death and lower CXCL1 (chemokine [C-X-C motif] ligand 1) release (downstream to IL-1α) than those exposed to wild-type platelets. In turn, MBL deposition on ischemic vessels significantly decreases after ischemia in mice treated with IL-1 receptor antagonist compared with controls, indicating a reciprocal interplay between MBL and IL-1α facilitating endothelial damage. Conclusions- We propose MBL as a hub of pathogenic vascular events. It acts as an early trigger of platelet IL-1α release, which in turn favors MBL deposition on ischemic vessels promoting an endothelial pro-inflammatory phenotype.

This study examines the direct effects of 3 noncompetitive N-methyl-D-aspartate receptor antagonists, phencyclidine (PCP), (+)MK-801, and (-)MK-801, on bovine middle cerebral arteries (BMCA). Rings of BMCA were mounted in isolated tissue chambers equipped with isometric tension transducers to obtain pharmacologic dose-response curves. In the absence of endogenous vasoconstrictors, the 3 N-methyl-D-aspartate antagonists each produced direct constriction of BMCA. The thromboxane A2 receptor antagonist SQ-29,548, the TxA2 synthase inhibitor furegrelate, the calcium antagonist nimodipine, and calcium-deficient media all inhibited maximal phencyclidine or (+)MK-801-induced constriction. Direct constriction by PCP or (+)MK-801 was independent of the presence of endothelium. When BMCA were preconstricted with potassium-depolarizing solution, PCP, (+)MK-801, and (-)MK-801 each produced only concentration-dependent relaxation. When BMCA were preconstricted with the stable TxA2 analog U-46,619 and exposed to increasing concentrations of PCP, (+)MK-801, or (-)MK-801, tension increased. Thromboxane A2 may contract BMCA by acting as a potassium channel blocker; iberiotoxin and tetraethylammonium both constrict BMCA. In Ca-deficient media containing either potassium or U-46,619, phencyclidine and (+)MK-801 each produced competitive inhibition of subsequent Ca-induced constriction. In additional experiments, arterial strips were mounted in isolated tissue chambers to directly measure calcium uptake, using Calcium as a radioactive tracer. Both phencyclidine and (+)MK-801 blocked potassium-stimulated or U-46,619-stimulated Ca uptake into arterial strips. These results suggest that phencyclidine and (+)MK-801 have 2 separate actions on BMCA. They may constrict arterial rings by releasing TxA2 from cerebrovascular smooth muscle, and relax arterial rings by acting as calcium antagonists.

Large conductance voltage- and calcium-gated channels (BK) control fundamental processes, including smooth muscle contractility and artery diameter. We used a baboon (Papio spp) model of pregnancy that is similar to that of humans to characterize BK channels in the middle cerebral artery and its branches in near-term (165 dGa) primate fetuses and corresponding pregnant mothers. In cell-attached patches (K+pipette = 135 mM) on freshly isolated fetal cerebral artery myocytes, BK currents were identified by large conductance, and voltage- and paxilline-sensitive effects. Their calcium sensitivity was confirmed by a lower Vhalf (transmembrane voltage needed to reach half-maximal current) in inside-out patches at 30 versus 3 μM [Ca2+]free. Immunostaining against the BK channel-forming alpha subunit revealed qualitatively similar levels of BK alpha protein-corresponding fluorescence in fetal and maternal myocytes. Fetal and maternal BK currents recorded at 3 μM [Ca2+]free from excised membrane patches had similar unitary current amplitude, and Vhalf. However, subtle differences between fetal and maternal BK channel phenotypes were detected in macroscopic current activation kinetics. To assess BK function at the organ level, fetal and maternal artery branches were pressurized in vitro at 30 mmHg and probed with the selective BK channel blocker paxilline (1 μM). The degree of paxilline-induced constriction was similar in fetal and maternal arteries, yet the constriction of maternal arteries was achieved sooner. In conclusion, we present a first identification and characterization of fetal cerebral artery BK channels in myocytes from primates. Although differences in BK channels between fetal and maternal arteries exist, the similarities reported herein advance the idea that vascular myocyte BK channels are functional near-term, and thus may serve as pharmacological targets during the perinatal-neonatal period., Competing Interests: The authors have declared that no competing interests exist.

The goal of the present study was to examine the effect of 1 wk of high salt (HS) intake and the role of oxidative stress in changing the mechanisms of flow-induced dilation (FID) in isolated pressurized middle cerebral arteries of male Sprague-Dawley rats ( n = 15-16 rats/group). Reduced FID in the HS group was restored by intake of the superoxide scavenger tempol (HS + tempol in vivo group). The nitric oxide (NO) synthase inhibitor N ω -nitro-l-arginine methyl ester, cyclooxygenase inhibitor indomethacin, and selective inhibitor of microsomal cytochrome P-450 epoxidase activity N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide significantly reduced FID in the low salt diet-fed group, whereas FID in the HS group was mediated by NO only. Cyclooxygenase-2 mRNA (but not protein) expression was decreased in the HS and HS + tempol in vivo groups. Hypoxia-inducible factor-1α and VEGF protein levels were increased in the HS group but decreased in the HS + tempol in vivo group. Assessment by direct fluorescence of middle cerebral arteries under flow revealed significantly reduced vascular NO levels and increased superoxide/reactive oxygen species levels in the HS group. These results suggest that HS intake impairs FID and changes FID mechanisms to entirely NO dependent, in contrast to the low-salt diet-fed group, where FID is NO, prostanoid, and epoxyeicosatrienoic acid dependent. These changes were accompanied by increased lipid peroxidation products in the plasma of HS diet-fed rats, increased vascular superoxide/reactive oxygen species levels, and decreased NO levels, together with increased expression of hypoxia-inducible factor-1α and VEGF. NEW & NOTEWORTHY High-salt (HS) diet changes the mechanisms of flow-induced dilation in rat middle cerebral arteries from a combination of nitric oxide-, prostanoid-, and epoxyeicosatrienoic acid-dependent mechanisms to, albeit reduced, a solely nitric oxide-dependent dilation. In vivo reactive oxygen species scavenging restores flow-induced dilation in HS diet-fed rats and ameliorates HS-induced increases in the transcription factor hypoxia-inducible factor-1α and expression of its downstream target genes.

Vasopressin (arginine vasopressin, AVP) plays a crucial role in maintaining body fluid homeostasis. Excessive release of vasopressin can lead to hyponatremia. Changes in cerebral circulation during vasopressin-induced chronic hyponatremia are not elucidated. The present study has been designed to investigate the effect of chronic vasopressin-induced hyponatremia on the regulation of the tone of the middle cerebral artery (MCA) of the rat. Chronic hyponatremia was induced in vivo with the help of vasopressin, released continuously from subcutaneously implanted ALZET mini-osmotic pumps, and a liquid diet. After 3.5 days of chronic hyponatremia, the plasma Na + concentration decreased to 119 ± 3 mM. MCAs were isolated and placed in a MOPS-buffered saline solution containing 121 mM Na + . Chronic hyponatremia did not affect the response of the MCA to increased intravascular pressure, to the administration of acetylcholine (ACh) and nitric oxide (NO) donor (SNAP, S-nitroso-N-acetyl-DL-penicillamine), and to increased K + concentration, but impaired the response of the MCA to increased extravascular H + concentration. Disturbed response of the MCA to acidosis was associated neither with the impairment of K ATP channels nor with the activation of vasopressin V 1 receptor. Correction of hyponatremia did not restore the response of the MCA to acidosis. These results indicate that cerebral blood vessels do not fully adapt to prolonged vasopressin-induced hyponatremia.

The increasing prevalence and severity of clinical depression are strongly correlated with vascular disease risk, creating a comorbid condition with poor outcomes but demonstrating a sexual disparity whereby female subjects are at lower risk than male subjects for subsequent cardiovascular events. To determine the potential mechanisms responsible for this protection against stress/depression-induced vasculopathy in female subjects, we exposed male, intact female, and ovariectomized (OVX) female lean Zucker rats to the unpredictable chronic mild stress (UCMS) model for 8 wk and determined depressive symptom severity, vascular reactivity in ex vivo aortic rings and middle cerebral arteries (MCA), and the profile of major metabolites regulating vascular tone. While all groups exhibited severe depressive behaviors from UCMS, severity was significantly greater in female rats than male or OVX female rats. In all groups, endothelium-dependent dilation was depressed in aortic rings and MCAs, although myogenic activation and vascular (MCA) stiffness were not impacted. Higher-resolution results from pharmacological and biochemical assays suggested that vasoactive metabolite profiles were better maintained in female rats with normal gonadal sex steroids than male or OVX female rats, despite increased depressive symptom severity (i.e., higher nitric oxide and prostacyclin and lower H 2 O 2 and thromboxane A 2 levels). These results suggest that female rats exhibit more severe depressive behaviors with UCMS but are partially protected from the vasculopathy that afflicts male rats and female rats lacking normal sex hormone profiles. Determining how female sex hormones afford partial vascular protection from chronic stress and depression is a necessary step for addressing the burden of these conditions on cardiovascular health. NEW & NOTEWORTHY This study used a translationally relevant model for chronic stress and elevated depressive symptoms to determine how these factors impact conduit and resistance arteriolar function in otherwise healthy rats. While chronic stress leads to an impaired vascular reactivity associated with elevated oxidant stress, inflammation, and reduced metabolite levels, we demonstrated partial protection from vascular dysfunction in female rats with normal sex hormone profiles compared with male or ovariectomized female rats.

While it is known that chronic stress and clinical depression are powerful predictors of poor cardiovascular outcomes, recent clinical evidence has identified correlations between the development of metabolic disease and depressive symptoms, creating a combined condition of severely elevated cardiovascular disease risk. In this study, we used the obese Zucker rat (OZRs) and the unpredictable chronic mild stress (UCMS) model to determine the impact of preexisting metabolic disease on the relationship between chronic stress/depressive symptoms and vascular function. Additionally, we determined the impact of metabolic syndrome on sex-based protection from chronic stress/depressive effects on vascular function in female lean Zucker rats (LZRs). In general, vasodilator reactivity was attenuated under control conditions in OZRs compared with LZRs. Although still impaired, conduit arterial and resistance arteriolar dilator reactivity under control conditions in female OZRs was superior to that in male or ovariectomized (OVX) female OZRs, largely because of better maintenance of vascular nitric oxide and prostacyclin levels. However, imposition of metabolic syndrome in combination with UCMS in OZRs further impaired dilator reactivity in both vessel subtypes to a similarly severe extent and abolished any protective effect in female rats compared with male or OVX female rats. The loss of vascular protection in female OZRs with UCMS was reflected in vasodilator metabolite levels, which closely matched those in male and OVX female OZRs subjected to UCMS. These results suggest that presentation of metabolic disease in combination with depressive symptoms can overwhelm the vasoprotection identified in female rats and, thereby, may reflect a severe impairment to normal endothelial function. NEW & NOTEWORTHY This study addresses the protection from chronic stress- and depression-induced vascular dysfunction identified in female compared with male or ovariectomized female rats. We determined the impact of preexisting metabolic disease, a frequent comorbidity of clinical depression in humans, on that vascular protection. With preexisting metabolic syndrome, female rats lost all protection from chronic stress/depressive symptoms and became phenotypically similar to male and ovariectomized female rats, with comparably poor vasoactive dilator metabolite profiles.

Background: Endovascular treatment for large-vessel acute ischemic stroke (AIS) has rapidly emerged. However, the understanding of the complex biology involving endothelial cells (ECs) remains scarce., Methods: Using stent retrievers during endovascular thrombectomy (ET) in patients with AIS, ECs were segregated, centrifuged in a dissociation buffer, and suspended in endothelial specific antibody solution. Subsequently, fluorescence-activated cell sorting (FACS) and microscopic analyses were performed., Results: Three stent-retriever devices (2 Solitaire, 1 Trevo) were collected as separate deployments. Of 5.0% (±.48%) total events using FACS, 6.8% (±.68%) of cells were specific for ECs using fluorescent markers and were further visualized on fluorescence microscopy for consistence with the positive controls., Conclusions: We describe a novel, minimally invasive biopsy technique to collect and harvest ECs from stent retrievers during ET and validate the approach in the treatment of AIS. Further work for detailed characterization and viability assessment of ECs is needed to compare their biology with in vitro and animal models., (Copyright © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

The Alpha Adrenergic Signaling Pathway is one of the chief regulators of cerebrovascular tone and cerebral blood flow (CBF), mediating its effects in the arteries through alpha1-adrenergic receptors (Alpha1AR). In the ovine middle cerebral artery (MCA), with development from a fetus to an adult, others and we have shown that Alpha1AR play a key role in contractile responses, vascular development, remodeling, and angiogenesis. Importantly, Alpha1AR play a significant role in CBF autoregulation, which is incompletely developed in a premature fetus as compared to a near-term fetus. However, the mechanistic pathways are not completely known. Thus, we tested the hypothesis that as a function of maturation and in response to Alpha1AR stimulation there is a differential gene expression in the ovine MCA. We conducted microarray analysis on transcripts from MCAs of premature fetuses (96-day), near-term fetuses (145-day), newborn lambs, and non-pregnant adult sheep (2-year) following stimulation of Alpha1AR with phenylephrine (a specific agonist). We observed several genes which belonged to pro-inflammatory and vascular development/angiogenesis pathway significantly altered in all of the four age groups. We also observed age-specific changes in gene expression-mediated by Alpha1AR stimulation in the different developmental age groups. These findings imply complex regulatory mechanisms of cerebrovascular development.

Background: Calcitonin gene-related peptide (CGRP) is one of the most potent endogenous vasodilators identified to date. The present study elucidates the differential interaction of CGRP, its receptor and the effect of the CGRP-receptor antagonist telcagepant on intracellular Ca 2+ -levels and tension in rat middle cerebral arteries (MCA) by pressurized arteriography, FURA-2/wire myography and immunohistochemistry., Methods: A pressurized arteriograph system was used to evaluate changes in MCA tension when subjected to CGRP and/or telcagepant. Intracellular calcium levels were evaluated using a FURA-2/wire myograph system. Localization of the CGRP-receptor components was verified using immunohistochemistry., Results: Abluminal but not luminal αCGRP (10 -12 -10 -6 M) caused concentration-dependent vasorelaxation in rat MCA. Luminal telcagepant (10 -6 M) failed to inhibit this relaxation, while abluminal telcagepant inhibited the relaxation (10 -6 M). Using the FURA-2 method in combination with wire myography we observed that αCGRP reduced intracellular calcium levels and in parallel the vascular tone. Telcagepant (10 -6 M) inhibited both vasorelaxation and drop in intracellular calcium levels. Both functional components of the CGRP receptor, CLR (calcitonin receptor-like receptor) and RAMP1 (receptor activity modifying peptide 1) were found in the smooth muscle cells but not in the endothelial cells of the cerebral vasculature., Conclusions: This study thus demonstrates the relaxant effect of αCGRP on rat MCA. The vasorelaxation is associated with a simultaneous decrease in intracellular calcium levels. Telcagepant reduced relaxation and thwarted the reduction in intracellular calcium levels localized in the vascular smooth muscle cells. In addition, telcagepant may act as a non-competitive antagonist at concentrations greater than 10 -8 M.

Purpose: Mapping brain hypoxia is a major goal for stroke diagnosis, pathophysiology and treatment monitoring. 18F-fluoro-misonidazole (FMISO) positron emission tomography (PET) is the gold standard hypoxia imaging method. Normobaric hyperoxia (NBO) is a promising therapy in acute stroke. In this pilot study, we tested the straightforward hypothesis that NBO would markedly reduce FMISO uptake in ischemic brain in Wistar and spontaneously hypertensive rats (SHRs), two rat strains with distinct vulnerability to brain ischemia, mimicking clinical heterogeneity., Methods: Thirteen adult male rats were randomized to distal middle cerebral artery occlusion under either 30% O2 or 100% O2. FMISO was administered intravenously and PET data acquired dynamically for 3hrs, after which magnetic resonance imaging (MRI) and tetrazolium chloride (TTC) staining were carried out to map the ischemic lesion. Both FMISO tissue uptake at 2-3hrs and FMISO kinetic rate constants, determined based on previously published kinetic modelling, were obtained for the hypoxic area. In a separate group (n = 9), tissue oxygen partial pressure (PtO2) was measured in the ischemic tissue during both control and NBO conditions., Results: As expected, the FMISO PET, MRI and TTC lesion volumes were much larger in SHRs than Wistar rats in both the control and NBO conditions. NBO did not appear to substantially reduce FMISO lesion size, nor affect the FMISO kinetic rate constants in either strain. Likewise, MRI and TTC lesion volumes were unaffected. The parallel study showed the expected increases in ischemic cortex PtO2 under NBO, although these were small in some SHRs with very low baseline PtO2., Conclusions: Despite small samples, the apparent lack of marked effects of NBO on FMISO uptake suggests that in permanent ischemia the cellular mechanisms underlying FMISO trapping in hypoxic cells may be disjointed from PtO2. Better understanding of FMISO trapping processes will be important for future applications of FMISO imaging.