High resolution simulation of basilar artery infarct and flow within the circle of Willis.

On a global scale, cerebro- and cardiovascular diseases have long been one of the leading causes of death and disability and their prevalence appears to be increasing in recent times. Understanding potential biomarkers and risk factors will help to identify individuals potentially at risk of suffering an ischemic stroke. However, the widely variable construction of the cerebral vasculature makes it difficult to provide a specific assessment without the knowledge of a patient's physiology. In this paper we use the 3D blood flow simulator HemeLB to study flow within three common structural variations of the circle of Willis during and in the moments after a blockage of the basilar artery. This tool, based on the lattice Boltzmann method, allows the 3D flow entering the basilar artery to be finely controlled to replicate the cessation of blood feeding this particular vessel-we demonstrate this with several examples including a sudden halt to flow and a gradual loss of flow over three heartbeat cycles. In this work we start with an individualised 3D representation of a full circle of Willis and then construct two further domains by removing the left or right posterior communicating arteries from this geometry. Our results indicate how, and how quickly, the circle of Willis is able to redistribute flow following such a stroke. Due to the choice of infarct, the greatest reduction in flow was observed in the posterior cerebral arteries where flow was reduced by up to 70% in some cases. The high resolution domains used in this study permit the velocity magnitude and wall shear stress to be analysed at key points during and following the stroke. The model we present here indicates how personalised vessels are required to provide the best insight into stroke risk for a given individual.

The regional effect of serum hormone levels on cerebral blood flow in healthy nonpregnant women.

Sex hormones estrogen (EST) and progesterone (PROG) have received increased attention for their important physiological action outside of reproduction. While studies have shown that EST and PROG have significant impacts on brain function, their impact on the cerebrovascular system in humans remains largely unknown. To address this, we used a multi-modal magnetic resonance imaging (MRI) approach to investigate the link between serum hormones in the follicular phase and luteal phase of the menstrual cycle (MC) with measures of cerebrovascular function (cerebral blood flow [CBF]) and structure (intracranial artery diameter). Fourteen naturally cycling women were recruited and assessed at two-time points of their MC. CBF was derived from pseudo-continuous arterial spin labeling while diameters of the internal carotid and basilar artery was assessed using time of flight magnetic resonance angiography, blood samples were performed after the MRI. Results show that PROG and EST had opposing and spatially distinct effects on CBF: PROG correlated negatively with CBF in anterior brain regions (r = -.86, p < .01), while EST correlations were positive, yet weak and most prominent in posterior areas (r = .78, p < .01). No significant correlations between either hormone or intracranial artery diameter were observed. These results show that EST and PROG have opposing and regionally distinct effects on CBF and that this relationship is likely not due to interactions with large intracranial arteries. Considering that CBF in healthy women appears tightly linked to their current hormonal state, future studies should consider assessing MC-related hormone fluctuations in the design of functional MRI studies in this population.

Identification of intima-to-media signals for flow-induced vascular remodeling using correlative gene expression analysis.

Changes in blood flow can induce arterial remodeling. Intimal cells sense flow and send signals to the media to initiate remodeling. However, the nature of such intima-media signaling is not fully understood. To identify potential signals, New Zealand white rabbits underwent bilateral carotid ligation to increase flow in the basilar artery or sham surgery (n = 2 ligated, n = 2 sham). Flow was measured by transcranial Doppler ultrasonography, vessel geometry was determined by 3D angiography, and hemodynamics were quantified by computational fluid dynamics. 24 h post-surgery, the basilar artery and terminus were embedded for sectioning. Intima and media were separately microdissected from the sections, and whole transcriptomes were obtained by RNA-seq. Correlation analysis of expression across all possible intima-media gene pairs revealed potential remodeling signals. Carotid ligation increased flow in the basilar artery and terminus and caused differential expression of 194 intimal genes and 529 medial genes. 29,777 intima-media gene pairs exhibited correlated expression. 18 intimal genes had > 200 medial correlates and coded for extracellular products. Gene ontology of the medial correlates showed enrichment of organonitrogen metabolism, leukocyte activation/immune response, and secretion/exocytosis processes. This demonstrates correlative expression analysis of intimal and medial genes can reveal novel signals that may regulate flow-induced arterial remodeling.

Methyl palmitate modulates the nicotine-induced increase in basilar arterial blood flow.

Methyl palmitate (MP) is a fatty acid methyl ester. Our recent study indicated that adrenergic nerve-dependent functional sympathetic-sensory nerve interactions were abolished by MP in mesenteric arteries. However, the effect of MP on perivascular nerves and cerebral blood flow remains unclear. In this study, the increase in basilar arterial blood flow (BABF) after the topical application of nicotinic acetylcholine receptor agonists was measured using laser Doppler flowmetry in anesthetized rats. The choline (a selective α7-nicotinic acetylcholine receptor agonist)-induced increase in BABF was abolished by tetrodotoxin (a neurotoxin), NG -nitro-L-arginine (a nonselective NO synthase inhibitor), α-bungarotoxin (a selective α7-nicotinic acetylcholine receptor inhibitor), and chronic sympathetic denervation. In addition, the nicotine (a nicotinic acetylcholine receptor agonist)-induced increase in BABF was inhibited by MP in a concentration-dependent manner. The acetylcholine-induced increase in BABF was not affected by MP. The myography results revealed that nicotine-induced vasorelaxation was significantly inhibited by MP, but was reversed by chelerythrine (a protein kinase C inhibitor). MP-induced vasodilation was significantly greater in BA rings without endothelium compared to those with endothelium. Meanwhile, MP did not affect baseline BABF. Our results indicate that MP acts as a neuromodulator in the cerebral circulation where it activates the PKC pathway and causes a diminished nicotine-induced increase in blood flow in the brainstem, and that the vasorelaxation effect of MP may play a minor role.

Velocity Pulsatility and Arterial Distensibility Along the Internal Carotid Artery.

Background Attenuation of velocity pulsatility along the internal carotid artery (ICA) is deemed necessary to protect the microvasculature of the brain. The role of the carotid siphon within the whole ICA trajectory in pulsatility attenuation is still poorly understood. This study aims to assess arterial variances in velocity pulsatility and distensibility over the whole ICA trajectory, including effects of age and sex. Methods and Results We assessed arterial velocity pulsatility and distensibility using flow-sensitized 2-dimensional phase-contrast 3.0 Tesla magnetic resonance imaging in 118 healthy participants. Velocity pulsatility index (vPI=(Vmax-Vmin)/Vmean) and arterial distensibility defined as area pulsatility index (Amax-Amin)/Amean) were calculated at C1, C3, and C7 segments of the ICA. vPI increased between C1 and C3 (0.85±0.13 versus 0.93±0.13, P<0.001 for averaged right+left ICA) and decreased between C3 and C7 (0.93±0.13 versus 0.84±0.13, P<0.001) with overall no effect (C1-C7). Conversely, the area pulsatility index decreased between C1 and C3 (0.18±0.06 versus 0.14±0.04, P<0.001) and increased between C3 and C7 (0.14±0.04 versus 0.31±0.09, P<0.001). vPI in men is higher than in women and increases with age (P<0.015). vPI over the carotid siphon declined with age but remained stable over the whole ICA trajectory. Conclusions Along the whole ICA trajectory, vPI increased from extracranial C1 up to the carotid siphon C3 with overall no effect on vPI between extracranial C1 and intracranial C7 segments. This suggests that the bony carotid canal locally limits the arterial distensibility of the ICA, increasing the vPI at C3 which is consequently decreased again over the carotid siphon. In addition, vPI in men is higher and increases with age.

Evaluation of basilar artery and cerebrospinal fluid dynamics using phase-contrast MRI: Comparison between mannitol and isotonic saline solution.

Increased intracranial pressure (ICP) can cause irreversible pathological changes in the canine brain and can be life-threatening, so prompt diagnosis and therapeutic responses are warranted. The purposes of this prospective experimental study were to evaluate phase-contrast MRI (PC-MRI) as a non-invasive method for quantifying cerebrospinal fluid (CSF) and basilar artery flow, and to assess effects of intravenous administration of hypertonic fluid. A PC-MRI scan was acquired for six healthy Beagle dogs at the level of the mesencephalic aqueduct. Either 1.0 g/kg mannitol or isotonic saline solution was administered intravenously for 15 min each at a matched dose volume of 5 mL/kg. Basilar artery and CSF flow rates were measured and their values compared between mannitol and isotonic saline solution groups before administration, and subsequently every 15 min for 2 h post-administration. The CSF dynamics were further assessed by measuring repeat flow from the caudal to rostral direction and the rostral to caudal direction as the number of waves. No significant difference was observed in basilar or and CSF flow velocity between the two groups (P > .05). However, administration of isotonic saline solution tended to increase basilar artery velocity slightly over time, while CSF velocity remained unchanged. In the mannitol group, CSF wave forms tended to be reduced at 60 and 75 min (P > .05). Findings from this preliminary study indicated that it is feasible to measure the dynamics of CSF and basilar artery flow by PC-MRI, but no flow differences could be detected for mannitol versus isotonic saline administration.

Vasodilation activity of dipfluzine metabolites in isolated rat basilar arteries and their underlying mechanisms.

Identifying the metabolites of a drug has become an indispensable task in the development of new drugs. Dipfluzine (Dip) is a promising candidate for the treatment of cerebral vascular diseases and has 5 metabolites (M1∼M5) in rat urine and liver microsomes, but their biological activity is still unknown. Because selective cerebral vasodilation is a main role of Dip, we investigated the vasodilation of Dip and its 5 metabolites in isolated Sprague-Dawley (SD) male rat basilar arteries preconstricted with high-K+ or 5-HT. The results showed that only M1 possessed concentration-dependent inhibitory activity on the vasoconstriction of arteries with or without the endothelium, and M1 has a more potent vasodilatory effect than Dip on both contraction models. Like Dip, the vasodilatory mechanisms of M1 may be not only related to receptor-operated and voltage-dependent calcium ion channels of smooth muscle cells but also to the release of NO and EDHF from endothelial cells and the opening of Ca2+-activated K+ channels and ATP-sensitive potassium ion channels. Unlike Dip, the vasodilation mechanism of M1 is also related to the opening of voltage-sensitive K+ channel. Together with more selectivity to non-VDCC than Dip, this may partially explain why M1 has stronger vasodilatory effects than Dip. The mechanisms of vasodilation of Dip and M1 may result from the combined action of these or other factors, especially blocking non-endothelium dependent non-VDCC and endothelium dependent IKCa channels. These results point to the possibility that M1 provides synergism for the clinical use of Dip, which may inform the synthesis of new drugs.

Epac-mediated relaxation in murine basilar arteries depends on membrane permeability of cyclic nucleotide analogues and endothelial aging.

Cerebral blood supply is finely tuned by regulatory mechanisms depending on vessel caliber the disruption of which contributes to the development of diseases such as vascular dementia, Alzheimer's and Parkinson 's diseases. This study scopes whether cAMP-mimetic-ligands relax young and aged murine cerebral arteries, whether this relates to the activation of PKA or Epac signaling pathways and is changed with advanced age. The hormone Urocortin-1 relaxed submaximally contracted young and old basilar arteries with a similar pD2 and DMAX (~ -8.5 and ~ 90% in both groups). In permeabilized arteries, PKA activation by 6-Bnz-cAMP or Epac activation by 8-pCPT-2'- O-Me-cAMP also induced relaxation with pD2 of -6.3 vs. -5.8 in old for PKA-ligands, and -4.4 and -4.0 in old for Epac-ligands. Furthermore, aging significantly increased submaximal Ca2+-induced force. The effect of 8-pCPT-2'-O-Me-cAMP on intact arteries was attenuated by aging or nitric oxide synthase inhibition. No relaxing effect in both age-groups was observed after treatment with PKAactivator, Sp-6-Phe-cAMPS. In conclusion, our results suggest that in intact basilar arteries relaxation induced by cAMP-mimetics refers only to the activation of Epac and is impaired by smooth muscle and endothelial aging. The study presents an interesting option allowing therapeutic discrimination between both pathways, possibly for the exclusive activation of Epac in brain circulatory system.

Determining the Optimal Normalization Factor of Different Target Arteries for ex vivo Vascular Function Experiments: A New Standardized Procedure.

The standardization of resistance vessel preparation is crucial to compare physiologic vascular reactivity under different experimental conditions. Here, we describe a generalizable experimental setup for ex vivo vascular function experiments and their mathematical basis. Porcine basilar arteries and chicken common carotid arteries were isolated post mortem via standardized surgical approaches. The inner circumference of these vessels with a passive wall tension corresponding to 100 mm Hg (IC100) as well as the circumference at which the active force production of the vessel is maximal (IC1) were determined systematically. The IC1/IC100 ratio (also referred to as factor k), a value that is believed to be constant for a defined vessel type in one species, was calculated by a novel mathematical approach. Here, we present an easy-to-use toolbox for the systematic and computer-based calculation of factor k and simplified optimal pre-stretching of any vascular segments for wire myography experiments.

Anti-high mobility group box-1 antibody attenuated vascular smooth muscle cell phenotypic switching and vascular remodelling after subarachnoid haemorrhage in rats.

Although cerebral vascular smooth muscle cell (VSMC) phenotypic switching is involved in the vascular dysfunction after subarachnoid haemorrhage (SAH), the precise mechanisms are still unclear. High mobility group box-1 (HMGB1) has been identified as a modulator in VSMC proliferation. The purpose of this study was to investigate the potential role of HMGB1 in the VSMC phenotypic switching following SAH. An endovascular perforation SAH model was used in our experiments. The expression levels of HMGB1, α-smooth muscle actin (α-SMA), osteopontin (OPN), smooth muscle myosin heavy chain (SM-MHC), embryonic smooth muscle myosin heavy chain (Smemb), TXA2, PAR-1 and AT1 receptor were evaluated by Western blot analyses. Iba1-positive cells and apoptotic cells were determined by immunofluorescence staining and TUNEL staining, respectively. Vasoconstriction of the isolated basilar artery was stimulated by thrombin and KCl. We found that HMGB1 expression was markedly increased following SAH, and anti-HMGB1 mAb significantly reversed VSMC phenotypic switching and vascular remodelling in rats. However, the effects of HMGB1 on VSMC phenotypic switching were partly blocked in the presence of SC79, a potent activator of phosphatidylinositol-3-kinase-AKT (PI3K/AKT). Furthermore, the enhanced vasoconstriction and decreased cerebral cortical blood flow induced by SAH were reversed by anti-HMGB1 mAb. Finally, we found that anti-HMGB1 mAb attenuated microglial activation and brain oedema, ameliorating neurological dysfunction. These results indicated that HMGB1 is a useful regulator of VSMC phenotypic switching and vascular remodelling following SAH and might be exploited as a novel therapeutic target for delayed cerebral ischaemia.

Stroke mechanisms and their correlation with functional outcome in medullary infarction.

PURPOSE: To study the stroke mechanism of medullary infarction (MI) and their correlation with prognosis. METHODS: We collected 81 consecutive patients with acute isolated MI including 50 patients with lateral MI (LMI), 30 with medial MI (MMI) and one with combined MI. The stroke mechanisms were defined as follows: 1. Large artery atherosclerotic occlusive disease (LAOD): with severe stenosis (>50%) or occlusion on the relevant arteries. 2. Penetrating artery disease (PAD): occlusion of penetrating arteries that arise from vertebral artery or basilar artery with no significant stenosis of the vertebro-basilar artery. 3. Dissection: angiographic findings met the criteria. 4. Cardiogenic embolism: abrupt onset with atrial fibrillation. The poor outcome was defined as a condition that includes the mRS ≥2 and/or dysphagia at one year after onset. RESULTS: There were 20 patients with PAD (40%), 18 with dissection (36.0%) and 11 with LAOD (22.0%) in LMI and 17 with PAD (56.6%), 10 with LAOD (33.3%) in MMI. LAOD and dissection compared with PAD were independently correlated with poor outcome in LMI (OR: 12.8, p = 0.029 and OR: 14.9, p = 0.035). LAOD was significantly correlated with poor outcome in MMI (OR: 13.4, p = 0.014). CONCLUSIONS: PAD was the most predominant stroke mechanism in MI and generally showed favorable outcome. Patients with LAOD and dissection showed worse outcome than those with PAD.

The Eurasian Elk's (Alces alces) Brain Base Arteries in View of Vascular Variation.

This article presents the results of analysis of the arterial vascular region of the Eurasian elk, which is a representative of the Cervidae family. The study was conducted on 39 Eurasian elks. The head arteries of 25 animals were filled with LBS 3040 synthetic latex. The head arteries of the other 14 Eurasian elks were filled with an acetone solution of stained chlorinated polyvinyl chloride and macerated. The arterial circle of the Eurasian elk's brain is composed of bilateral rostral cerebral arteries and caudal communicating arteries. The basilar artery closes the arterial circle caudally. The rostral cerebral artery first ramifies into the rostral choroidal artery, then, the middle cerebral artery and the rostral communicating artery. The caudal cerebral artery and the rostral cerebellar artery branch off the caudal communicating artery. The arterial pattern of the Eurasian elk's brain base is similar to the arteries found in other deer. Like in other Ruminantia, the rostral epidural rete mirabile is a unique structure in the Eurasian elk's arterial system. Anat Rec, 302:339-345, 2019. © 2018 Wiley Periodicals, Inc.

Focal adhesions are involved in simulated-microgravity-induced basilar and femoral arterial remodelling in rats.

Recent studies have suggested that microgravity-induced arterial remodelling contributes to post-flight orthostatic intolerance and that multiple mechanisms are involved in arterial remodelling. However, the initial mechanism by which haemodynamic changes induce arterial remodelling is unknown. Focal adhesions (FAs) are dynamic protein complexes that have mechanotransduction properties. This study aimed to investigate the role of FAs in simulated-microgravity-induced basilar and femoral arterial remodelling. A 4-week hindlimb-unweighted (HU) rat model was used to simulate the effects of microgravity, and daily 1-hour intermittent artificial gravity (IAG) was used to prevent arterial remodelling. After 4-week HU, wall thickness, volume of smooth muscle cells (SMCs) and collagen content were increased in basilar artery but decreased in femoral artery (P < 0.05). Additionally, the expression of p-FAK Y397 and p-Src Y418 was increased and reduced in SMCs of basilar and femoral arteries, respectively, by HU (P < 0.05). The number of FAs was increased in basilar artery and reduced in femoral artery by HU (P < 0.05). Furthermore, daily 1-hour IAG prevented HU-induced differential structural adaptations and changes in FAs of basilar and femoral arteries. These results suggest that FAs may act as mechanosensors in arterial remodelling by initiating intracellular signal transduction in response to altered mechanical stress induced by microgravity.

A novel antihypertension agent, sargachromenol D from marine brown algae, Sargassum siliquastrum, exerts dual action as an L-type Ca2+ channel blocker and endothelin A/B2 receptor antagonist.

We isolated the novel vasoactive marine natural products, (5E,10E)-14-hydroxy-2,6,10-trimethylpentadeca-5,10-dien-4-one (4) and sargachromenol D (5), from Sargassum siliquastrum collected from the coast of the East Sea in South Korea by using activity-guided HPLC purification. The compounds effectively dilated depolarization (50mMK+)-induced basilar artery contraction with EC50 values of 3.52±0.42 and 1.62±0.63µM, respectively, but only sargachromenol D (5) showed a vasodilatory effect on endothelin-1 (ET-1)-induced basilar artery contraction (EC50=9.8±0.6µM). These results indicated that sargachromenol D (5) could act as a dual antagonist of l-type Ca2+ channel and endothelin A/B2 receptors. Moreover, sargachromenol D (5) lowered blood pressure in spontaneous hypertensive rats (SHRs) 2h after oral treatment at a dose of 80mg/kg dose and the effect was maintained for 24h. Based on our ex vivo and in vivo experiments, we propose that sargachromenol D (5) is a strong candidate for the treatment of hypertension that is not controlled by conventional drugs, in particular, severe-, type II diabetes-, salt-sensitive, and metabolic disease-induced hypertension.

Vessel shape alterations of the vertebrobasilar arteries in Mucopolysaccharidosis type IVa (Morquio A) patients.

PURPOSE: Main symptom of mucopolysaccharidosis type IVa (MPS IVa) is progressive systemic skeletal dysplasia. This is routinely monitored by cerebral and spinal MRI. The vascular system is generally not in the primary focus of interest. In our population of MPS IVa patients we observed vessel shape alterations of the vertebrobasilar arteries, which has not been described before. MATERIAL AND METHODS: MRI-datasets of 26 patients with MPS IVa acquired between 2008 and 2015 were eligible for retrospective analysis of the vertebrobasilar arteries. The vessel length and angle of the basilar artery (BA) and both vertebral arteries (VA) were analyzed. A deflection angle between 90° and 130° in the vessel course was defined as tortuosity, less than 90° as kinking. The results were compared to a matched control group of 23 patients not suffering from MPS. RESULTS: The deflection angle [°] of the VA and BA was significantly decreased in the majority (85%) of MPS IVa patients compared to the control group: BA 132±24 vs. 177±6, BA/VA transition 113±21 vs. 152±13, right VA 108±23 vs. 156±13, left VA 110± 22 vs. 157±14 (all p<0.005). Likewise, vessels of MPS IVa patients were significantly longer compared to the control group: BA 27±4 vs. 21±2, right VA 20±6 vs. 10±1, left VA 18±5 vs. 11±2 (all p<0.005). CONCLUSION: MPS IVa is associated with significantly increased tortuosity of vertebrobasilar arteries. Therefore the vascular system of MPS IVa patients should be monitored on routinely basis, as vessel shape alterations had been associated with dissections, leading to a higher risk of cerebrovascular events.

Vascular territorial segmentation and volumetric blood flow measurement using dynamic contrast enhanced magnetic resonance angiography of the brain.

This study proposes a method for territorial segmentation and volumetric flow rate (VFR) distribution measurement of cerebral territories based on time-resolved contrast enhanced magnetic-resonance-angiography (MRA). The method uses an iterative region-growing algorithm based on bolus-arrival-time with increased temporal resolution. Eight territories were segmented: (1) right and (2) left internal carotid arteries, including the middle cerebral artery (ICA+MCA), excluding the anterior cerebral arteries (ACA); (3) right and left ACA (R+L-ACA); (4) right and (5) left external carotid arteries (ECA); (6) right and (7) left posterior cerebral arteries (PCA); and (8) vertebrobasilar territory. VFR percentage, relative to the entire brain (rVFR), was measured based on territorial volume as a function of time. Mean rVFR values of fifteen healthy subjects were: ICA+MCA = 23 ± 2%, R + L-ACA = 17 ± 3%, ECA = 4 ± 2%, PCA = 12 ± 2%, and vertebrobasilar territory = 31 ± 4%. Excluding the ECA-rVFR, which is underestimated, these values are comparable to previously reported values. Six subjects were scanned twice, demonstrating comparable and even higher reproducibility than previously reported using phase-contrast, yet with faster scan time (∼1 min). This method was implemented in one patient with MCA occlusion and one with Moyamoya syndrome scanned before and after bypass surgery, demonstrating its clinical potential for quantitative assessment of the degree of occlusion and the effect of surgery.

Aging-related alterations in eNOS and nNOS responsiveness and smooth muscle reactivity of murine basilar arteries are modulated by apocynin and phosphorylation of myosin phosphatase targeting subunit-1.

Aging causes major alterations of all components of the neurovascular unit and compromises brain blood supply. Here, we tested how aging affects vascular reactivity in basilar arteries from young (<10 weeks; y-BA), old (>22 months; o-BA) and old (>22 months) heterozygous MYPT1-T-696A/+ knock-in mice. In isometrically mounted o-BA, media thickness was increased by ∼10% while the passive length tension relations were not altered. Endothelial denudation or pan-NOS inhibition (100 µmol/L L-NAME) increased the basal tone by 11% in y-BA and 23% in o-BA, while inhibition of nNOS (1 µmol/L L-NPA) induced ∼10% increase in both ages. eNOS expression was ∼2-fold higher in o-BA. In o-BA, U46619-induced force was augmented (pEC50 ∼6.9 vs. pEC50 ∼6.5) while responsiveness to DEA-NONOate, electrical field stimulation or nicotine was decreased. Basal phosphorylation of MLC20-S19 and MYPT1-T-853 was higher in o-BA and was reversed by apocynin. Furthermore, permeabilized o-BA showed enhanced Ca2+-sensitivity. Old T-696A/+ BA displayed a reduced phosphorylation of MYPT1-T696 and MLC20, a lower basal tone in response to L-NAME and a reduced eNOS expression. The results indicate that the vascular hypercontractility found in o-BA is mediated by inhibition of MLCP and is partially compensated by an upregulation of endothelial NO release.

Doppler Sonography of Blood Flow Velocity in the Vertebral Arteries of Preterm and Term Neonates.

OBJECTIVES: This study aimed to evaluate normal blood flow in the vertebral arteries and the basilar artery of preterm and term neonates by Doppler sonography. METHODS: Blood flow in both vertebral arteries and the basilar artery was examined in 102 neonates between the biological ages of 28 and 41 weeks. Fifty-one boys and 51 girls underwent Doppler sonography. Measurements were usually undertaken at 6 days old. Systolic and diastolic flow velocities, including the resistive index, were measured and analyzed, taking into consideration biological age, weight, and sex. Anatomic aberrations of the vertebral arteries were recorded. RESULTS: Mean blood flow values ± SD in the basilar artery were 35.2 ± 7.4 cm/s (systolic velocity) and 10.9 ± 3.5 cm/s (diastolic velocity). Mean blood flow values in the right vertebral artery were 26.8 ± 9.3 cm/s (systolic velocity) and 8.0 ± 3.7 cm/s (diastolic velocity). Mean blood flow values in the left vertebral artery were 28.6 ± 8.3 cm/s (systolic velocity) and 8.7 ± 3.3 cm/s (diastolic velocity). Systolic and diastolic blood flow in both vertebral arteries was significantly higher from 38 to 41 weeks compared with 28 to 32 and 33 to 37 weeks (P < .05). Regression analysis of systolic and diastolic blood flow velocities in the vertebral arteries versus biological age yielded significant results (P < .05). CONCLUSIONS: Sonography is an excellent tool for examining blood flow in the basilar and vertebral arteries of premature and term neonates. Mean systolic and diastolic blood flow velocities in the vertebral arteries increase significantly with age.

Nuclear factor-κB is involved in oxyhemoglobin-induced endothelin-1 expression in cerebrovascular muscle cells of the rabbit basilar artery.

The present research was designed to investigate whether endothelin-1 (ET-1) secretion can be induced by oxyhemoglobin and whether nuclear factor κB (NF-κB) is involved in the regulation of ET-1 transcription in cerebrovascular muscle cells. Cerebrovascular muscle cells isolated from a rabbit basilar artery were stimulated by oxyhemoglobin (OxyHb) and ET-1 production was increased significantly in the supernatant. Inhibition of NF-κB with pyrrolidine dithiocarbamate and small interfering RNA decreased the expression of ET-1. Nuclear translocation of NF-κB and the degradation of IkB-α was observed with the stimulation of OxyHb. The supernatant obtained from cerebrovascular muscle cells stimulated by OxyHb produced contractions in arterial rings and was blocked by the ET-1 receptor antagonist (BQ-123). The time course of the OxyHb-induced contractions of the basilar artery rings correlated with the time course of the OxyHb-induced ET-1 secretion. The contraction of the basilar artery rings induced by OxyHb was attenuated when the artery rings were preincubated with pyrrolidine dithiocarbamate and SN50 (20 and 10 µM, respectively). These results indicate that cerebrovascular muscle cells may be an important source of ET-1 production after subarachnoid hemorrhage. NF-κB was involved in the expression of ET-1 and the inhibition of the NF-κB pathway may be beneficial for the treatment of cerebral vasospasm.

Relaxant Effects of the Selective Estrogen Receptor Modulator, Bazedoxifene, and Estrogen Receptor Agonists in Isolated Rabbit Basilar Artery.

We have previously shown that the selective estrogen receptor modulator, bazedoxifene, improves the consequences of ischemic stroke. Now we aimed to characterize the effects and mechanisms of action of bazedoxifene in cerebral arteries. Male rabbit isolated basilar arteries were used for isometric tension recording and quantitative polymerase chain reaction. Bazedoxifene relaxed cerebral arteries, as 17-ß-estradiol, 4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol [estrogen receptor (ER) α agonist], and G1 [G protein-coupled ER (GPER) agonist] did it (4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol > bazedoxifene = G1 > 17-ß-estradiol). 2,3-Bis(4-hydroxyphenyl)-propionitrile (ERß agonist) had no effect. Expression profile of genes encoding for ERα (ESR1), ERß (ESR2), and GPER was GPER > ESR1 > ESR2. As to the endothelial mechanisms, endothelium removal, N-nitro-L-arginine methyl ester, and indomethacin, did not modify the relaxant responses to bazedoxifene. As to the K channels, both a high-K medium and the Kv blocker, 4-aminopyridine, inhibited the bazedoxifene-induced relaxations, whereas tetraethylammonium (nonselective K channel blocker), glibenclamide (selective KATP blocker) or iberiotoxin (selective KCa blocker) were without effect. Bazedoxifene also inhibited both Ca- and Bay K8644-elicited contractions. Therefore, bazedoxifene induces endothelium-independent relaxations of cerebral arteries through (1) activation of GPER and ERα receptors; (2) increase of K conductance through Kv channels; and (3) inhibition of Ca entry through L-type Ca channels. Such a profile is compatible with the beneficial effects of estrogenic compounds (eg, SERMs) on vascular function and, specifically, that concerning the brain. Therefore, bazedoxifene could be useful in the treatment of cerebral disorders in which the cerebrovascular function is compromised (eg, stroke).