Reactivity Of Middle Cerebral Artery Research Articles

Prenatal dexamethasone exposure impaired vascular reactivity in adult male offspring cerebral arteries

BackgroundCerebrovascular disease is one of the leading causes of death worldwide. Middle cerebral artery (MCA) is the largest and most complex of cerebral arteries. The prenatal period is a critical time for development, which largely determines lifelong health. Clinically, glucocorticoids (GCs) administration to accelerate preterm fetal lung maturation has become standard practice. Prenatal GCs administration increases cardiovascular risks in offspring, but little is known regarding the side effects on offspring MCA function. ObjectiveWe investigated the alterations of MCA reactivity following prenatal GCs administration in postnatal offspring. Method and resultsPregnant Sprague-Dawley rats received synthetic GCs (dexamethasone, DEX) during the last week of pregnancy, and we examined vascular reactivity, cellular electrophysiology, and gene promoter epigenetic modifications in the male offspring MCA. Our results showed that prenatal DEX exposure increased the sensitivity of offspring MCA to Angiotensin II, which was resulted from the increased Cav1.2 (L-type Ca2+ channels subunit alpha1 C). Mechanistically, prenatal DEX exposure resulted in a transcriptionally active chromatin structure at the Cav1.2 gene promoter by altering histone modifications. This activation led to increased expression of vascular Cav1.2 gene, ultimately resulting in increased MCA contractility in offspring. ConclusionThe present study is the first to demonstrate that the adverse effects of prenatal GCs administration on cerebrovascular tone persist into adulthood, providing new insights into developmental origins of cerebrovascular disease.

Sex differences in middle cerebral artery reactivity and hemodynamics in 6-month-old Sprague-Dawley rats independent from systemic arterial stiffness or blood pressure

Cerebrovascular disease (CVD) is a major risk factor for developing cognitive impairment. Young women are protected against CVD compared with older women or men, however the underlying mechanisms are not well understood. Greater peripheral arterial stiffness has been linked to increased cerebral flow pulsatility and cognitive impairment. In this study we determined whether sex differences in middle cerebral artery (MCA) reactivity are associated with changes in cerebral [MCA, intracranial internal carotid artery (ICA)] or systemic [common carotid artery (CCA), thoracic aorta (TAo)] arterial resistance and stiffness in six month-old Sprague-Dawley (SD) rats. No differences in systolic or diastolic blood pressures measured by tail-cuff method were observed between sexes. Heart rate was higher in the female versus male SD (438±9 vs. 343±10 bpm, p<0.05, n=8-12). The pulsatility (PI) and resistance indexes (RI) of left MCA and left intracranial ICA were calculated as follows: PI=(Peak systolic velocity (Vs)-End-diastolic velocity (Vd))/Vmean, or RI=(Vs-Vd)/Vs (Vevo LAZR, FUJIFILM VisualSonics). Left MCA PI and RI indexes were lower in the female versus male SD (PI: 0.75±0.09 vs. 1.17±0.11; RI: 0.49±0.04 vs. 0.63±0.03, all p<0.05; n=7-8), while no differences in left ICA blood flow (n=4-9) or resistance (n=7-10) were observed between sexes. There were no differences in arterial stiffness of TAo or left CCA evaluated by pulse wave velocity (PWV) measurements. To investigate vascular reactivity, left MCA segments were isolated and mounted on a wire Multi Myograph (DMT-USA). Data were acquired and analyzed with Powerlab 8 and LabChart v8 (ADInstruments). Female left MCA had lower contraction to potassium (K+: 0.6±0.1 vs. 1±0.2 mN/mm, p<0.05), but similar maximal contraction (109±10 vs. 116±6 %KMAX, p>0.05) and sensitivity (7.3±0.2 vs. 7.2±0.2, p>0.05) to thromboxane A2 receptor agonist U46619. Pre-incubation with indomethacin lowered maximal response (97±5 vs. 116±6 %KMAX, p<0.05) and sensitivity (6.8±0.1 vs. 7.2±0.2, p<0.05) to U46619 in male MCA, with no effect in female MCA (Male: 109±9 vs. 113±7 %KMAX; Female: 7.3±0.2 vs. 7.3±0.2). MCA collagen deposition (by trichrome staining) was similar between sexes, however eNOS immunoreactivity tended to increase in the female versus male MCA (7.3±2 vs. 1.2±0.6; n=3-4, p=0.07). No sex differences in MCA COX-2 expression were found. In summary, lower PI and RI of MCA in 6-month-old females suggests decreased cerebrovascular resistance compared with age-matched male SD. Increased eNOS expression may contribute to the lower contraction observed in female MCA, whereas vasoconstrictor prostaglandins appear to have a greater role in male versus female MCA. Our results demonstrate sex differences in MCA vascular reactivity associated with a protective functional profile of MCA in 6-month-old female versus male SD rats independent from changes in systemic arterial stiffness or blood pressure. Studies were supported by the WFUSM CVSC Pilot Award and NIH 5R01HL155420. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Increased cerebral vascular resistance underlies preserved cerebral blood flow in response to orthostasis in humans on a high-salt diet.

Cerebral blood flow autoregulation protects brain tissue from blood pressure variations and maintains cerebral perfusion pressure by changes in vascular resistance. High salt (HS) diet impairs endothelium-dependent vasodilation in many vascular beds, including cerebral microcirculation, and may affect vascular resistance. The aim of present study was to determine if 7-day HS diet affected the reactivity of middle cerebral artery (MCA) to orthostatic challenge in healthy human individuals, and if autoregulatory mechanisms and sympathetic neural regulation were involved in this phenomenon.Twenty-seven persons participated in study (F:21, M:6, age range 19-24). Participants consumed 7-day low-salt (LS) diet (< 2.3g kitchen salt/day) and afterwards 7-day HS diet (> 11.2g kitchen salt/day). Blood and urine analysis and anthropometric measurements were performed after each diet. Arterial blood pressure, heart rate and heart rate variability, and cerebral and systemic hemodynamic parameters were recorded simultaneously with transcranial Doppler ultrasound and The Task Force®Monitor in response to orthostatic test.Participants remained normotensive during HS diet. Following both, the LS and HS dietary protocols, mean cerebral blood flow (CBF), as well as the velocity time integral and diastolic blood pressure decreased, and cerebral pulsatility index increased after rising up. Importantly, cerebrovascular resistance significantly increased in response to orthostasis only after HS diet. Urine concentration of noradrenaline and vanillylmandelic acid, baroreflex sensitivity (BRS), and sympathetic neural control was significantly decreased in HS diet.Results suggest that CBF in response to orthostatic test was preserved in HS condition due to altered vascular reactivity of MCA, with increased cerebrovascular resistance and blunted BRS and sympathetic activity.

Refractory and resistant hypertension in patients with type 2 diabetes mellitus: differences in metabolic profile and endothelial function

To determine the prevalence of refractory hypertension (RfH) in patients with and without type 2 diabetes mellitus (DM), as well as to evaluate whether diabetic patients with RfH significant differ from those with uncontrolled resistant hypertension (RH) in clinical phenotype, metabolic profile and endothelial function. The study included 193 patients with RH: RH 74 patients with diabetes and 119 patients without DM. Uncontrolled RH and RfH were defined by the presence of uncontrolled blood pressure BP (140 and/or 90 mm Hg) despite the use of 3 but 5 antihypertensive drugs (for RH) and 5 antihypertensive drugs, including a mineralocorticoid receptor antagonist (for RfH). Clinical examination, lab tests were performed. Flow-mediated dilation (FMD) and vasoreactivity of middle cerebral artery (MCA) using both breath-holding and hyperventilation test were measured by high-resolution ultrasound. The prevalence of refractory hypertension in patients with and without DM was similar (30% vs 28%, respectively). No differences in BP levels, data of echocardiography and clinical phenotype were found between the diabetic groups, but value of HOMA index, plasma resistin level and postprandial glycaemia were higher in patients with RfH. FMD and MCA reactivity to the breath-holding test were worse in patients with RfH, and they had a more pronounced vasoconstrictor response of MCA to the hyperventilation test compared to patients with RH. The prevalence of RfH is the same in patients with and without diabetes. Diabetic patients with refractory hypertension have a more unfavorable metabolic profile and greater impairment of endothelial function than patients with uncontrolled resistant hypertension.

Age‐Associated Changes in Cerebrovascular Function and BK Channel Function are Sex‐Specific

Large conductance potassium (BK) channels are known to regulate the myogenic reactivity, yet, it is not clear if 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. We used vascular reactivity, patch‐clamp, and biochemical methods to measure the myogenic reactivity, BK channel function, and expression, respectively, in cerebral vessels of adult and aged male and female Sprague Dawley rats. The results suggest that aging and ovariectomy (OVX) exaggerated the myogenic reactivity of middle cerebral arteries (MCA) in females but attenuated it in males. Aging induced outward eutrophic remodeling in females but inward hypertrophic remodeling 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 content both in males and females. However, aging decreased BKβ1 subunit protein and mRNA levels 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. OVX decreased, but chronic supplementation of estradiol (OVX+17βE rats) restored BK channel expression and function. BKβ1 mRNA is decreased in cerebral vessels of OVX rats that is consistent with decreased protein content. However, supplementation with 17βE did not increase mRNA, but protein is not decreased suggesting that post‐translational mechanisms contribute to the preservation of the protein. Overall the results suggest that aging and OVX‐associated downregulation of the BKβ1 expression and function in females exaggerates the myogenic reactivity of MCA. However, age‐associated increase in BK channel function in males attenuates the myogenic reactivity of MCA.Support or Funding InformationThis work was supported by, in part, by a grant from the Intramural Research Support Program from UMMC and AHA Scientist Development Grant 13SDG14000006 (M. R. Pabbidi).

Endothelium-dependent impairments to cerebral vascular reactivity with type 2 diabetes mellitus in the Goto-Kakizaki rat.

Type 2 diabetes mellitus (T2DM) is a prevalent pathology associated with elevated cerebrovascular disease risk. We determined wall mechanics and vascular reactivity in ex vivo middle cerebral arteries (MCA) from male Goto-Kakizaki rats (GK; ~17 wk old) versus control Wistar Kyoto rats (WKY) to test the hypothesis that the diabetic environment in GK, in the absence of obesity and other comorbidities, leads to endothelial dysfunction and impaired vascular tone regulation. Dilation of MCA following challenge with acetylcholine and hypoxia was blunted in MCA from GK versus WKY, due to lower nitric oxide bioavailability and altered arachidonic acid metabolism, whereas myogenic activation and constrictor responses to serotonin were unchanged. MCA wall distensibility and cross-sectional area were not different between GK and WKY, suggesting that wall mechanics were unchanged at this age, supported by the determination that MCA dilation to sodium nitroprusside was also intact. With the use of ex vivo aortic rings as a bioassay, altered vascular reactivity determined in MCA was paralleled by relaxation responses in artery segments from GK, whereas measurements of vasoactive metabolite production indicated a loss of nitric oxide and prostacyclin bioavailability and an increased thromboxane A2 production with both methacholine challenge and hypoxia. These results suggest that endothelium-dependent dilator reactivity of MCA in GK is impaired with T2DM, and that this impairment is associated with the genesis of a prooxidant/pro-inflammatory condition with diabetes mellitus. The restriction of vascular impairments to endothelial function only, at this age and development, provide insight into the severity of multimorbid conditions of which T2DM is only one constituent.

Abstract TMP115: Nox-2 and Cerebrovascular Function in Metabolic Syndrome After a Stroke

Introduction: The aim here is to elucidate the mechanisms involved in post-stroke cerebrovascular impairments in metabolic syndrome (MetS) that pre-dispose obese patients to more severe post-stroke deficits. Methods: 1 hr middle cerebral artery occlusion was performed in 17 week old lean (LZR) and obese Zucker (OZR: MetS model) rats. At 24 hr or 15 days post-stroke, the ipsilateral middle cerebral artery (MCA) was cannulated in an ex-vivo microvessel preparation to examine MCA reactivity. Cerebrovascular microvessel density (MVD) was examined 15 days post-stroke via IHC. To examine a potential role of Nox2 and oxidative stress, a specific inhibitor of Nox2 oxidase Nox2-dstat (i.p 10mg/kg) was given during the stroke procedure in OZR. Results: In LZR, MCA reactivity was impaired vs. non-stroke control at 24hr post-stroke and remained stable at 15 days post-stroke. In LZR, NO bioavailability was reduced at 24hrs vs. controls, which remained stable at 15 days. In OZR, the MCA impairment was greater at 24 hr vs. LZR, and worsened significantly at 15 days post stroke. NO bioavailability for OZR at 24 hr was similar to LZR stroke, but by 15 days had fallen. MVD was reduced 15 days post-stroke, with a larger loss in OZR vs. LZR. Stroke mortality and infarct size were higher for OZR. Nox2 inhibition restored MCA reactivity, improved MVD and NO levels, and limited stroke infarct size in OZR post-stroke. Discussion: Our data suggest that the MetS increases stroke severity and drives a progressive decline in cerebrovascular dysfunction following ischemic stroke. Inhibiting Nox2 production improved stroke outcome in MetS.

Attenuated flow-induced dilatation of middle cerebral arteries is related to increased vascular oxidative stress in rats on a short-term high salt diet.

Recent studies have shown that high salt (HS) intake leads to endothelial dysfunction and impaired vascular reactivity in different vascular beds in both animal and human models, due to increased oxidative stress. The objective of this study was to assess vascular response to flow-induced dilatation (FID) and to elucidate the role of vascular oxidative stress/antioxidative capacity in middle cerebral arteries (MCAs) of HS-fed rats in vitro. The novelty of this study is in demonstrating impaired flow-induced dilatation of MCAs and down-regulation of vascular antioxidant genes with HS intake, leading to increased levels of oxidative stress in blood vessels and peripheral lymph organs, which together contribute to impaired FID. In addition, results show increased oxidative stress in leukocytes of peripheral lymph organs, suggesting the occurrence of inflammatory processes due to HS intake. Recirculation of leukocytes might additionally increase vascular oxidative stress in vivo. The aim of this study was to determine flow-induced dilatation (FID) and the role of oxidative stress/antioxidative capacity in isolated, pressurized middle cerebral arteries (MCAs) of high salt (HS)-fed rats. Healthy male Sprague-Dawley rats (11weeks old) were fed low salt (0.4% NaCl; LS group) or high salt (4% NaCl; HS group) diets for 1week. Reactivity of MCAs in response to stepwise increases in pressure gradient (Δ10-Δ100mmHg) was determined in the absence or presence of the superoxide dismutase (SOD) mimetic TEMPOL and/or the nitric oxide synthases (NOS) inhibitor N(ω) -nitro-l-arginine methyl ester (l-NAME). mRNA levels of antioxidative enzymes, NAPDH-oxidase components, inducible (iNOS) and endothelial nitric oxide synthases (eNOS) were determined by quantitative real-time PCR. Blood pressure (BP), antioxidant enzymes activity, oxidative stress in peripheral leukocytes, lipid peroxidation products and the antioxidant capacity of plasma were measured for both groups. FID was reduced in the HS group compared to the LS group. The presence of TEMPOL restored dilatation in the HS group, with no effect in the LS group. Expression of glutathione peroxidase 4 (GPx4) and iNOS in the HS group was significantly decreased; oxidative stress was significantly higher in the HS group compared to the LS group. HS intake significantly induced basal reactive oxygen species production in the leukocytes of mesenteric lymph nodes and splenocytes, and intracellular production after stimulation in peripheral lymph nodes. Antioxidant enzyme activity and BP were not affected by HS diet. Low GPx4 expression, increased superoxide production in leukocytes, and decreased iNOS expression are likely to underlie increased oxidative stress and reduced nitric oxide bioavailability, leading to impairment of FID in the HS group without changes in BP values.

Effects of Early Post-Ischemic Reperfusion and tPA on Cerebrovascular Function and Nitrosative Stress in Female Rats.

Stroke is a major health issue in women. Our previous studies in male rats showed decreased myogenic tone in middle cerebral arteries (MCAs) after ischemia and reperfusion (I/R), while tone in parenchymal arterioles (PAs) was increased. This vascular response may aggravate stroke damage in males by limiting reperfusion; however, the effect in females is not known. The current study investigated the effect of I/R and tissue plasminogen activator (tPA) on myogenic tone and reactivity of MCAs and PAs in female rats. Nitrosative stress by peroxynitrite and recruitment of inflammatory neutrophils to the microvasculature were also studied. Female rats were subjected to 2-h MCA filament occlusion (n = 16) or sham surgery (n = 17) and given tPA (1mg/kg, i.v) or vehicle followed by 30-min reperfusion. Myogenic tone and reactivity were measured in isolated and pressurized MCAs and PAs from the same animals. Cerebrovascular F-actin, 3-nitrotyrosine (3-NT, peroxynitrite marker), and intravascular neutrophils were quantified. Myogenic tone and constriction to the nitric oxide synthase inhibitor Nω-nitro-L-arginine were decreased in MCAs but unchanged in PAs after I/R with no effect of tPA. F-actin and 3-NT expression were unaffected by I/R or tPA. Our study showed that MCAs from females, similar to what has been seen in males, are dilated after I/R and have decreased myogenic tone while tone in PAs was unchanged. Increased small vessel resistance may contribute to decreased reperfusion and worse outcome after stroke.

Relationship between deep medullary veins in susceptibility-weighted imaging and ipsilateral cerebrovascular reactivity of middle cerebral artery in patients with ischemic stroke.

Deep cerebral veins have been recently associated with the severity of hemodynamic impairment in moyamoya disease. The aim of the current study was to determine the correlation of deep medullary veins (DMVs) in susceptibility-weighted imaging (SWI) with ipsilateral cerebrovascular reactivity (CVR) of and anterior cecebrocervical artery stenosis in patients with ischemic stroke. Patients with unilateral TIA or infarction who underwent 3.0 T magnetic resonance imaging SWI, digital subtraction angiography and transcranial Doppler with CO2 stimulation within the first 7 days of hospitalization were retrospectively selected. CVR and stenosis of anterior cerebrocervical arteries were compared between different DMVs stages in symptomatic hemispheres (SHs) and asymptomatic hemispheres (AHs). A total of 61 patients were subsequently included in the present study. A univariate analysis was conducted and results for age (PAHs=0.004, PSHs=0.006), hypertension (PAHs=0.008, PSHs=0.020), current smoking (PAHs=0.006, PSHs=0.021), CVR (PAHs=0.000, PSHs=0.000), and artery stenosis (PAHs=0.000, PSHs=0.000) were obtained. The results suggested statistically significant differences between DMVs grades in SHs and AHs. A subsequent multivariate analysis revealed that CVR (ORAHs=0.925, 95% CIAHs: 0.873–0.981; ORSHs=0.945, 95% CISHs: 0.896–0.996), and artery stenosis (ORAH=3.147, 95% CIAH: 1.010–9.806; ORSHs=2.882, 95% CISHs: 1.017–8.166) were independent risk factors of DMVs. In conclusion, 3.0 T SWI was useful in detecting the DMVs around the lateral ventricle in patients with atherosclerotic ischemic stroke. CVR and stenosis of anterior cerebrocervical arteries were independent risk factors for ipsilateral DMVs in SHs and AHs.

Determination of Vascular Reactivity of Middle Cerebral Arteries from Stroke and Spinal Cord Injury Animal Models Using Pressure Myography.

Stroke and other neurovascular derangements are main causes of global death. They, along with spinal cord injuries, are responsible for being the principal cause of disability due to neurological and cognitive problems. These problems then lead to a burden on scarce financial resources and societal care facilities as well as have a profound effect on patients' families. The mechanism of action in these debilitating diseases is complex and unclear. An important component of these problems arises from derangement of blood vessels, such as blockage due to clotting/embolism, endothelial dysfunction, and overreactivity to contractile agents, as well as alteration in endothelial permeability. Moreover, the cerebro-vasculature (large vessels and arterioles) is involved in regulating blood flow by facilitating auto-regulatory processes. Moreover, the anterior (middle cerebral artery and the surrounding region) and posterior (basilar artery and its immediate locality) regions of the brain play a significant role in triggering the pathological progression of ischemic stroke particularly due to inflammatory activity and oxidative stress. Interestingly, modifiable and non-modifiable cardiovascular risk factors are responsible for driving ischemic and hemorrhagic stroke and spinal cord injury. There are different stroke animal models to examine the pathophysiology of middle cerebral and basilar arteries. In this context, arterial myography offers an opportunity to determine the etiology of vascular dysfunction in these diseases. Herein, we describe the technique of pressure myography to examine the reactivity of cerebral vessels to contractile and vasodilator agents and a prelude to stroke and spinal cord injury.

Captopril treatment improves endothelium dependent dilation and middle cerebral artery remodeling in hypertensive rats (841.8)

Hypertension is associated with cognitive deficits. Angiotensin converting enzyme inhibitors (ACEI) improve cognitive decline in hypertensive patients. We hypothesized that centrally active ACEI captopril (CTP) would alleviate cognitive function by improving endothelium dependent dilation and middle cerebral artery (MCA) remodeling from stroke prone spontaneously hypertensive rats (SHRSP). Data are shown as mean±SEM, SHRSP vs CTP and are analyzed by Student’s t‐test. 12 week old male SHRSP received CTP (50 mg/kg/day) for 6 weeks. Cognitive function, evaluated by Morris water maze, showed no difference between groups. CTP reduced systolic blood pressure (178±8 vs 131±6 mmHg, p&lt;0.05). MCA reactivity and passive structure was assessed by pressure myography (data shown at 80 mmHg). CTP did not increase lumen diameter (232.6±8.1 vs 249.1±8.1). CTP reduced wall thickness (21.9±0.1 vs 17.3±1.0 µm, p&lt;0.05) and wall/lumen ratio (0.1±0.01 vs 0.07±0.01, p&lt;0.05). CTP improved endothelial function as evidenced by enhanced dilation to 10 µM adenosine diphosphate (change in diameter from baseline at: 36.2±1.0 vs 54.2± 5.3 µm, p&lt;0.05). CTP increased resting pial artery perfusion (673±32 vs 750±201 laser Doppler units, p&lt;0.05). These data suggests that while CTP does not affect cognitive abilities, it may contribute to increased baseline perfusion by enhancing dilation and reversing remodeling of MCAs.

Transient Focal Cerebral Ischemia Induces Long-term Cerebral Vasculature Dysfunction in a Rodent Experimental Stroke Model

Constriction and dilation of large arteries of brain regulates cerebral vascular resistance and cerebral microvascular pressure, which play key roles in regulation of cerebral circulation. We investigated the effect of ischemic stroke on vascular reactivity of middle cerebral artery (MCA) using a rat transient focal cerebral ischemia model. Focal cerebral ischemia was induced by 1 hour MCA occlusion followed by reperfusion. MCAs were dissected from ischemic or contralateral hemisphere at 2 days or 2 weeks post reperfusion and mounted on 2 glass micropipettes for assessment of vascular reactivity. MCAs from brains of sham surgeries were used as control. At 2 days post reperfusion, a significant alteration of myogenic reactivity was found in MCAs dissected from both ischemic and non-ischemic hemispheres, which could still be identified at 2 weeks after reperfusion. Phenylephrine (PE) induced remarkable vasoconstriction in MCAs from animals that underwent sham surgery. No significant alteration of vasoconstrictive response to PE was found in MCAs isolated from either ischemic or contralateral hemisphere at 2 days or 2 weeks after ischemic stroke, as compared with MCAs from sham animals. Acetylcholine (ACh) induced mild dilation in normal MCAs, which was reversed in MCAs from both ischemic and non-ischemic hemispheres at 2 weeks after ischemic stroke. Sodium nitroprusside (SNP) induced vasodilation in MCAs from animals with sham operation, which was diminished in MCAs from both ischemic and non-ischemic hemisphere at 2 days and 2 weeks after ischemic stroke. These results demonstrated that focal cerebral ischemia could induce long-term global cerebral vasculature dysfunction.

Effects of vitamin E on the response of the fetal middle cerebral artery to the pressure test

Objective. To examine the effects of the maternal administration of vitamin E on the vasoreactivity of the middle cerebral artery (MCA) in preterm fetuses.Study design. The vasoconstrictive response of the proximal segment of the MCA to brief and partial external occlusions of the umbilical vein (pressure test) was studied in 22 fetuses between 21 and 35 weeks of gestation, before, and 3 to 7 days after, the maternal administration of oral vitamin E (50 mg daily).Results. The vasoconstrictive activity of the MCA was eliminated in 15 fetuses (68.2%), unchanged in six (27.3%), and decreased in one (4.5%). In the latter seven cases, vasoconstriction of the proximal MCA in response to the pressure test was eliminated by increasing the vitamin E dosage to 100 mg/day.Conclusion. Vitamin E administered to the mothers had a pronounced effect on the proximal MCA reactivity in preterm fetuses.

Pharmacological neutropenia prevents endothelial dysfunction but not smooth muscle functions impairment induced by middle cerebral artery occlusion

1. The polymorphonuclear neutrophils (PMN) activation and mobilization observed in acute cerebral infarction contribute to the brain tissue damage, but PMN could also be involved in postischemic functional injury of ischemied blood vessel. 2. This study was undertaken to investigate whether pharmacological neutropenia could modify the postischemic endothelial dysfunction in comparison to smooth muscle whose impairment is likely more related to reperfusion and oxidative stress. 3. A cerebral ischemia-reperfusion by endoluminal occlusion of right middle cerebral artery (MCA) was performed 4 days after intravenous administration of vinblastine or 12 h after RP-3 anti-rat neutrophils monoclonal antibody (mAb RP-3) injection into the peritoneal cavity, on male Wistar rats with 1-h ischemia then followed by 24-h reperfusion period. Brain infarct volume was measured by histomorphometric analysis and vascular endothelial and smooth muscle reactivity of MCA was analysed using Halpern myograph. 4. Neutropenia induced a neuroprotective effect as demonstrated by a significant decrease of brain infarct size. In parallel to neuroprotection, neutropenia prevented postischemic impairment of endothelium-dependent relaxing response to acetylcholine. In contrast, smooth muscle functional alterations were not prevented by neutropenia. Ischemia-reperfusion-induced myogenic tone impairment remained unchanged in vinblastine and mAb RP-3-treated rats. Postischemic Kir2.x-dependent relaxation impairment was not prevented in neutropenic conditions. The fully relaxation of smooth muscle response to sodium nitroprusside was similar in all groups. 5. Our results evidenced the dissociate prevention of pharmacologically induced neutropenia on postischemic vascular endothelial and smooth muscle impairment. The selective endothelial protection by neutropenia is parallel to a neuroprotective effect suggesting a possible relationship between the two phenomena.

Oxidant stress and constrictor reactivity impair cerebral artery dilation in obese Zucker rats

This study tested the hypothesis that evolution of the metabolic syndrome in obese Zucker rats (OZR) leads to impaired dilator reactivity of cerebral resistance arteries vs. responses determined in lean Zucker rats (LZR). Middle cerebral arteries (MCA) from 17-wk-old male LZR and OZR were isolated and cannulated with glass micropipettes. Vascular reactivity was assessed in response to challenge with ACh, sodium nitroprusside (SNP), reductions and elevations in Po2, 5-HT, and increased intralumenal pressure. Vessels were treated with the free radical scavenger 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (tempol) to assess the role of superoxide production in altering reactivity, and passive vascular wall mechanics was assessed in each vessel. Vascular superoxide production was assessed in isolated arteries using fluorescence microscopy. Vessel dilation to ACh and hypoxia was impaired in OZR vs. LZR, although responses to SNP were normal. Vessel constriction to 5-HT, elevated Po2, and elevated intralumenal pressure was enhanced in OZR vs. LZR. Fluorescence microscopy demonstrated an increased superoxide production in arteries of OZR vs. LZR, correctable by incubation with tempol. Although treatment of vessels from OZR with tempol improved dilation to ACh and hypoxia, constrictor responses to 5-HT, elevated Po2, and pressure were not altered by tempol treatment. Indexes of vessel wall mechanics were comparable between groups. These results suggest that vasodilator reactivity of MCA of OZR in response to endothelium-dependent dilator stimuli is impaired vs. LZR and that this may represent a reduced bioavailability of signaling molecules due to oxidant scavenging. However, oxidative stress-independent increases in myogenic tone and constrictor reactivity may contribute to blunted dilator responses of cerebral microvessels.

Basilar and middle cerebral artery reactivity in patients with migraine.

Migraine has been reported as a possible risk factor for ischemic stroke. The mechanisms underlying this association are unknown. To evaluate cerebrovascular reactivity to hypercapnia in the anterior and posterior circulation of patients with migraine, as reduced cerebrovascular reactivity is associated with a predisposition to stroke in various clinical conditions. Using transcranial Doppler ultrasonography, changes in flow velocity during apnea were measured in both middle cerebral arteries and in the basilar artery of 15 control subjects and 30 patients with migraine (15 with aura and 15 without aura) during an attack-free period. Cerebrovascular reactivity was evaluated using the breath-holding index, which is calculated by dividing the percent increase in mean flow velocity recorded during a breath-holding episode by its duration (in seconds) after a normal inspiration. Vascular reactivity in the middle cerebral arteries was similar in patients and controls and significantly lower in the basilar artery of patients with migraine with aura compared with the other 2 groups (P <.0001). These findings show that in patients with migraine with aura, there is an impairment in the adaptive cerebral hemodynamic mechanisms in the posterior circulation. This fact could have pathogenetic implications since the association between migraine and stroke frequently regards patients with migraine with aura, and cerebral infarcts occur more commonly in the vertebrobasilar district.

Involvement of thrombolysis in recombinant tissue plasminogen activator-induced cerebral hemorrhages and effect on infarct volume and postischemic endothelial function.

In a model of mechanical focal ischemia, we investigated the involvement of thrombolysis products (TLP) in recombinant tissue plasminogen activator (rtPA)-induced intracerebral complications and the effects on infarct volume and postischemic endothelial function. Hemorrhage incidence and severity were evaluated by histomorphometric analysis in male spontaneously hypertensive rats (SHR) subjected to 60-minute intraluminal middle cerebral artery (MCA) occlusion and receiving intravenously 5 hours later either saline, rtPA (3, 10, or 30 mg/kg), or rtPA (10 mg/kg) associated with TLP (rtPA+TLP). In addition, MCA reactivity was assessed in rtPA- or rtPA+TLP-treated SHR versus control Wistar-Kyoto rats or SHR. No hemorrhage was observed visually in SHR receiving saline. In contrast, rtPA administration induced hemorrhagic complications in infarcted areas in a dose-independent manner. Administration of rtPA+TLP solution, containing a high concentration of plasmin, did not affect hemorrhage incidence but significantly increased hemorrhage severity (8.8+/-2.3 petechiae versus 3.0+/-1.0 petechiae in rtPA group; P<0.001). This increased severity was associated with a significant increase of both infarct volume (182+/-10 versus 144+/-15 mm3 in rtPA group; P<0.01) and postischemic impairment of MCA endothelium-dependent relaxation (9+/-0.5% versus 13+/-1% in rtPA group; P<0.05). Treatment with rtPA led to intracerebral hemorrhages, in contrast to saline-treated animals, and the presence of TLP increased the severity of these hemorrhages, in parallel with increased infarct volume and worsened endothelial function.

Preserved contractility without side bias in endovascular filament models for subarachnoid hemorrhage

It is currently unknown whether endovascular filament (EF) models of acute subarachnoid hemorrhage (SAH) introduce any ‘side bias’ upon cerebrovascular reactivity by virtue of unilateral carotid manipulation, unilateral EF insertion, or potentially ipsilateral site of intracranial rupture. In this study, three experimental groups of adult male wistar rats were used: non-operated controls ( n=20), sham operated controls ( n=8), and SAH groups ( n=26). All were anaesthetized with intraperitoneal 25% urethane (1 g/kg) except n=2 anaesthetized with intraperitoneal hypnorm/hypnovel. SAH was created by advancing an intraluminal thread through the intracranial internal carotid artery from an extracranial source in the neck. Using in vitro wire myography in all three groups, middle cerebral artery (MCA) responses ipsilateral and contralateral to EF insertion were compared using a range of vasoconstrictors and vasodilators within 3 h of SAH. No significant side differences in MCA reactivity were found with any agent in any group or sub-group analysed. In conclusion, EF-SAH models do not appear to introduce any significant ‘side bias’ upon ipsilateral MCA reactivity by virtue of the potentially confounding combination: (1) unilateral carotid manipulation, (2) unilateral EF insertion or (3) potentially ipsilateral intracranial rupture. They may thus be more confidentally used for post-SAH ex vivo cerebral vessel study—acute or delayed.

Mapping of cerebrovascular reactivity using bold magnetic resonance imaging

Blood oxygen level-dependent (BOLD) contrast MRI is a simple non-invasive method of estimating “perfusion,” and combined with a vasodilatory stimulus, may allow estimation of cerebral vascular reserve. We compared BOLD carbon dioxide (CO 2) reactivity in the middle cerebral artery (MCA) perfusion territory to MCA flow velocity reactivity determined using transcranial Doppler ultrasound (TCD) in 16 patients with unilateral carotid artery stenosis or occlusion. Both BOLD and TCD reactivities were calculated from measurements acquired when the subjects were breathing air, and again when breathing a 6% CO 2/air mixture, and were normalized by dividing by the difference in end tidal (ET) CO 2. There was a significant correlation between interhemispheric MCA reactivity difference (contralateral–ipsilateral to the stenosis or occlusion) determined by BOLD MRI and TCD (r = 0.75, p < 0.001). In contrast, treating each hemisphere individually, there was no correlation between the absolute BOLD and TCD MCA CO 2 reactivities (r = 0.08, p = 0.670). This appeared to be due to a variable BOLD signal change in the non-stenosed hemisphere between subjects, with little change in the normal hemisphere of a few subjects. In one patient, focal regions of reduced reactivity were seen in non-infarcted regions of the stenosed hemisphere, in the borderzones between arterial territories. BOLD reactivity maps provide information on the whole MCA territory reactivity, and may identify small regions of impaired reactivity which are not detected using TCD. However, BOLD reactivity maps only appear to provide semi-quantitative rather than quantitative data.