Dilation Of Cerebral Arteries Research Articles

KATP channels in cerebral hemodynamics: a systematic review of preclinical and clinical studies.

Cumulative evidence suggests that ATP-sensitive potassium (KATP) channels act as a key regulator of cerebral blood flow (CBF). This implication seems to be complicated, since KATP channels are expressed in several vascular-related structures such as smooth muscle cells, endothelial cells and pericytes. In this systematic review, we searched PubMed and EMBASE for preclinical and clinical studies addressing the involvement of KATP channels in CBF regulation. A total of 216 studies were screened by title and abstract. Of these, 45 preclinical and 6 clinical studies were included. Preclinical data showed that KATP channel openers (KCOs) caused dilation of several cerebral arteries including pial arteries, the middle cerebral artery and basilar artery, and KATP channel inhibitor (KCI) glibenclamide, reversed the dilation. Glibenclamide affected neither the baseline CBF nor the baseline vascular tone. Endothelium removal from cerebral arterioles resulted in an impaired response to KCO/KCI. Clinical studies showed that KCOs dilated cerebral arteries and increased CBF, however, glibenclamide failed to attenuate these vascular changes. Endothelial KATP channels played a major role in CBF regulation. More studies investigating the role of KATP channels in CBF-related structures are needed to further elucidate their actual role in cerebral hemodynamics in humans. Systematic review registration: Prospero: CRD42023339278 (preclinical data) and CRD42022339152 (clinical data).

Effect of Intrathecal Eugenol on Cerebral Vasospasm in an Experimental Subarachnoid Hemorrhage Model

Eugenol has various curative properties. It affects the dilatation of cerebral arteries by voltage-dependent Ca2+ channel inhibition. This study is the first to explore the impact of eugenol on neuroprotection and vasospasm in an experimental subarachnoid hemorrhage (SAH) model. Twenty-four adult male Sprague-Dawley rats were indiscriminately separated into 3 groups: the control group (n = 8), the SAH group (n = 8), and the eugenol group (n = 8). A double bleeding method was used. The eugenol group received intracisternal eugenol (Sigma-Aldrich, St. Louis, MO, USA) at 30μg/20μl after induction of SAH. On the 7th day, all groups were euthanized. Measurements were taken for basilar artery wall thickness, lumen diameter, serum endothelin-1, and caspase-3 levels. The eugenol group exhibited significantly lower wall thickness, endothelin-1, oxidative stress index, and caspase-3 levels compared to the SAH group. In comparison to the control group, the eugenol group showed a higher oxidative stress index along with higher endothelin-1, and caspase-3 levels, but these differences were not statistically significant. Wall thickness was significantly higher in the eugenol group than in the control group. This study represents the first literature exploration of intrathecal eugenol's impact on vasospasm induced after experimental SAH. Administration of intrathecal eugenol demonstrates a positive effect on treatment of experimental vasospasm, as well as on reduction of oxidative stress and apoptosis.

Exploring the causal role of immune cells in cerebral aneurysm through single-cell transcriptomics and Mendelian randomization analysis.

Cerebral aneurysm (CA) represents a significant clinical challenge, characterized by pathological dilation of cerebral arteries. Recent evidence underscores the crucial involvement of immune cells in CA pathogenesis. This study aims to explore the complex interplay between immune cells and CA formation. We analyzed single-cell RNA sequencing data from the GSE193533 dataset, focusing on unruptured CA and their controls. Comprehensive cell-type identification and pseudo-time trajectory analyses were conducted to delineate the dynamic shifts in immune cell populations. Additionally, a two-sample Mendelian randomization (MR) approach was employed to investigate the causal influence of various immunophenotypes on CA susceptibility and the reciprocal effect of CA formation on immune phenotypes. Single-cell transcriptomic analysis revealed a progressive loss of vascular smooth muscle cells (VSMCs) and an increase in monocytes/macrophages (Mo/MΦ) and other immune cells, signifying a shift from a structural to an inflammatory milieu in CA evolution. MR analysis identified some vital immunophenotypes, such as CD64 on CD14+ CD16+ monocytes (OR: 1.236, 95% CI: 1.064-1.435, P = 0.006), as potential risk factors for CA development, while others, like CD28- CD8br %CD8br (OR: 0.883, 95% CI: 0.789-0.988, P = 0.030), appeared protective. Reverse MR analysis demonstrated that CA formation could modulate specific immunophenotypic expressions, highlighting a complex bidirectional interaction between CA pathology and immune response. This study underscores the pivotal role of immune cells in this process through the integration of single-cell transcriptomics with MR analysis, offering a comprehensive perspective on CA pathogenesis, and potentially guiding future therapeutic strategies targeting specific immune pathways.

Transfusion-Associated Reversible Cerebral Vasoconstriction Syndrome in Pediatrics: A Case Report and Review of Literature

Background Reversible cerebral vasoconstriction syndrome (RCVS) is a rare complication of packed red blood cell (pRBC) transfusion primarily reported in adults with severe chronic anemia due to menorrhagia. It is characterized by a triad of rapidly changing and reversible segmental cerebral artery narrowing and dilatation, thunderclap headache, and benign cerebrospinal fluid findings. 1,2 More than 50% of patients experience blurring of vision or cortical vision loss, and a subset of patients develop hemiparesis or aphasia. 1 There are emerging case reports of RCVS in pediatric patients, however the literature examining this transfusion complication in children is limited. The rarity and potential severity of RCVS warrants better understanding by pediatric hematology and transfusion providers. Results We describe a previously healthy 4 year-old male who presented with pallor and laboratory parameters consistent with severe iron deficiency anemia. Chest x-ray showed cardiomegaly, and echocardiogram demonstrated pericardial effusion, moderate left ventricular dilation, and moderate coronary artery dilatation. His history was notable for an extremely selective diet and at least 50 ounces of cow's milk daily. The patient was admitted, and over the course of 3 days, he received a total of 43 mL/kg of pRBCs (602 mL total) in 8 aliquots, and his hemoglobin (Hgb) increased from 1.4 g/dL to 11.4 g/dL (Fig. 1). He then re-presented 5 days after discharge with altered mental status and malignant hypertension. Brain MRI/MRA was consistent with RCVS, with luminal irregularities in multiple anterior and posterior circulation intracranial arteries creating a beaded appearance. He was treated supportively with aggressive blood pressure control and made a complete neurologic recovery 8 days after presentation. At hematology clinic follow-up 2 months post-discharge, he remained at his typical neurologic baseline. Conclusions The connection between blood transfusion and RCVS is postulated to be due to a rapid increase in hematocrit and blood viscosity, which alters cerebral autoregulation and leads to hypertensive encephalopathy despite systemic normotension. 3 The increased viscosity may also lead to vasospasm. 3 When a patient with severe chronic anemia receives a pRBC transfusion, there is increased cerebral blood flow and viscosity, resulting in decreased vasodilation, increased vascular resistance, and cerebral vessel constriction. However, these are hypothesized mechanisms with little supportive experimental data. Vasculopathies and vasoconstrictive medications 2 are also risk factors for RCVS. There are 4 previous reported cases of pediatric RCVS associated with pRBC transfusion. 2 patients were acutely ill with complications of sickle cell anemia. 7,9 Another case occurred in a patient with systemic lupus erythematosus 8, and the fourth occurred in the setting of severe iron deficiency anemia. 5 Several features of our patient's clinical course are similar to the reported cases of transfusion-related RCVS 5 and warrant highlighting: 1) severe chronic anemia with cardiac dysfunction and 2) the large volume of transfused pRBCs over a short period resulting in a significant increase in Hgb. However, our patient developed symptoms of RCVS sooner than other published cases and did not have seizure or stroke. Pediatric guidelines recommend pRBC transfusion for Hgb levels between 5-10 g/dL, depending on the clinical scenario. 4 There are few data to guide Hgb targets for pediatric patients presenting with severe anemia. Over-transfusion does not offer physiological benefit and poses risk of transfusion-related adverse events. A case report from Dou et al 6 proposed that a >5 g/dL Hgb increase was associated with a greater likelihood of developing RCVS. For this patient with cardiac dysfunction and social concerns including lack of primary care, the potential benefits of achieving a higher Hgb with pRBC transfusions were prioritized. RCVS should be considered in pediatric and adult patients recently transfused for chronic severe anemia presenting with headaches or other neurological symptoms. Prompt recognition of RCVS may prevent unnecessary treatment and potentially limit risk of neurologic compromise. The role of the volume and rapidity of the pRBC transfusions in the development of RCVS warrants further study. Fig 1. Timeline of initial presentation, detailing blood transfusions

Differential Functional Contribution of BK Channel Subunits to Aldosterone-Induced Channel Activation in Vascular Smooth Muscle and Eventual Cerebral Artery Dilation.

Calcium/voltage-activated potassium channels (BK) control smooth muscle (SM) tone and cerebral artery diameter. They include channel-forming α and regulatory β1 subunits, the latter being highly expressed in SM. Both subunits participate in steroid-induced modification of BK activity: β1 provides recognition for estradiol and cholanes, resulting in BK potentiation, whereas α suffices for BK inhibition by cholesterol or pregnenolone. Aldosterone can modify cerebral artery function independently of its effects outside the brain, yet BK involvement in aldosterone's cerebrovascular action and identification of channel subunits, possibly involved in steroid action, remains uninvestigated. Using microscale thermophoresis, we demonstrated that each subunit type presents two recognition sites for aldosterone: at 0.3 and ≥10 µM for α and at 0.3-1 µM and ≥100 µM for β1. Next, we probed aldosterone on SM BK activity and diameter of middle cerebral artery (MCA) isolated from β1-/- vs. wt mice. Data showed that β1 leftward-shifted aldosterone-induced BK activation, rendering EC50~3 μM and ECMAX ≥ 10 μM, at which BK activity increased by 20%. At similar concentrations, aldosterone mildly yet significantly dilated MCA independently of circulating and endothelial factors. Lastly, aldosterone-induced MCA dilation was lost in β1-/- mice. Therefore, β1 enables BK activation and MCA dilation by low µM aldosterone.

Papaverine: A Miraculous Alkaloid from Opium and Its Multimedicinal Application.

The pharmacological actions of benzylisoquinoline alkaloids are quite substantial, and have recently attracted much attention. One of the principle benzylisoquinoline alkaloids has been found in the unripe seed capsules of Papaver somniferum L. Although it lacks analgesic effects and is unrelated to the compounds in the morphine class, it is a peripheral vasodilator and has a direct effect on vessels. It is reported to inhibit the cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) phosphodiesterase in smooth muscles, and it has been observed to increase intracellular levels of cAMP and cGMP. It induces coronary, cerebral, and pulmonary artery dilatation and helps to lower cerebral vascular resistance and enhance cerebral blood flow. Current pharmacological research has revealed that papaverine demonstrates a variety of biological activities, including activity against erectile dysfunction, postoperative vasospasms, and pulmonary vasoconstriction, as well as antiviral, cardioprotective, anti-inflammatory, anticancer, neuroprotective, and gestational actions. It was recently demonstrated that papaverine has the potential to control SARS-CoV-2 by preventing its cytopathic effect. These experiments were carried out both in vitro and in vivo and require an extensive understanding of the mechanisms of action. With its multiple mechanisms, papaverine can be considered as a natural compound that is used to develop therapeutic drugs. To validate its applications, additional research is required into its precise therapeutic mechanisms as well as its acute and chronic toxicities. Therefore, the goal of this review is to discuss the major studies and reported clinical studies looking into the pharmacological effects of papaverine and the mechanisms of action underneath these effects. Additionally, it is recommended to conduct further research via significant pharmacodynamic and pharmacokinetic studies.

A challenging case of recurrent and progressive fusiform anterior circulation intracranial aneurysms: illustrative case.

Intracranial fusiform aneurysms are circumferential dilations of cerebral arteries that can lead to complications including ischemic stroke due to vessel occlusion, subarachnoid hemorrhage, or intracerebral hemorrhage. Treatment options for fusiform aneurysms have expanded significantly in recent years. Microsurgical treatment options include proximal and distal surgical occlusion and microsurgical trapping of the aneurysm, usually in association with high-flow bypass procedures. Endovascular treatment options include the placement of coils and/or flow diverters. Here the authors report a case of aggressive surveillance and treatment of a man with multiple progressive, recurrent, and de novo fusiform aneurysms of the left anterior cerebral circulation over 16 years. Because the long-term course of his treatment coincided with the recent expansion of endovascular treatment options, he underwent every type of treatment listed above. This case demonstrates the wide range of therapeutic options for fusiform aneurysms and how the treatment model for these lesions has evolved.

Aldosterone activates cerebrovascular smooth muscle BK channels in absence of β1 subunits, yet these potentiate steroid action and thus facilitate aldosterone-induced dilation of cerebral arteries.

Calcium/voltage-gated, big conductance K+ channels (BK α subunits or slo1 proteins) modulate smooth muscle (SM) tone and thus cerebral artery diameter. In cerebral arteries, the BK current phenotype is conditioned by regulatory β1 subunits which fine-tune channel activity to tissue-specific physiology. Several physiological steroids modify BK function and may modify cerebral artery function. Thus, cholesterol and pregnenolone inhibit SM BK and evoke middle cerebral artery (MCA) constriction through recognition by slo1 whereas estradiol and cholanes activate SM BK through recognition by β1. Aldosterone is a steroid with documented vasoactive properties, yet the involvement of BK in aldosterone's cerebrovascular action and the contribution of distinct channel subunits to this action remain unknown. Here, we first used nanoscale differential scanning fluorimetry to test whether aldosterone (0.3-100 μM) could directly bind BK α or β1 subunits. Changes in temperature of onset and inflection point (indicators of protein-steroid binding) were evident at 10 and 1 µM aldosterone for α and β1. Next, MCA SM cells were enzymatically isolated from mice, and cell-free recordings were conducted to determine changes in BK activity by aldosterone. Increased activity by aldosterone was concentration-dependent: EC50 = 3 μM; ECMAX = 10 μM, at which activity increased by 20%. Consistently with this small yet reproducible SM BK activation, 10 μM aldosterone dilated MCA by 2%, independently of circulating and endothelial factors. In SM cells and MCA segments from β1-/- mice, aldosterone activated BK with reduced potency and efficacy, and vasodilation by the steroid was evoked by very high concentrations (>>10 µM). Therefore, aldosterone is able to activate SM BK in absence of β1, yet this regulatory subunit potentiates aldosterone action and thus enables subµM-µM aldosterone to dilate MCA.

Endothelial cell TRPA1 activity exacerbates cerebral hemorrhage during severe hypertension.

Introduction: Hypoxia-induced dilation of cerebral arteries orchestrated by Ca2+-permeable transient receptor potential ankyrin 1 (TRPA1) cation channels on endothelial cells is neuroprotective during ischemic stroke, but it is unknown if the channel has a similar impact during hemorrhagic stroke. TRPA1 channels are endogenously activated by lipid peroxide metabolites generated by reactive oxygen species (ROS). Uncontrolled hypertension, a primary risk factor for the development of hemorrhagic stroke, is associated with increased ROS production and oxidative stress. Therefore, we hypothesized that TRPA1 channel activity is increased during hemorrhagic stroke. Methods: Severe, chronic hypertension was induced in control (Trpa1 fl/fl) and endothelial cell-specific TRPA1 knockout (Trpa1-ecKO) mice using a combination of chronic angiotensin II administration, a high-salt diet, and the addition of a nitric oxide synthase inhibitor to drinking water. Blood pressure was measured in awake, freely-moving mice using surgically placed radiotelemetry transmitters. TRPA1-dependent cerebral artery dilation was evaluated with pressure myography, and expression of TRPA1 and NADPH oxidase (NOX) isoforms in arteries from both groups was determined using PCR and Western blotting techniques. In addition, ROS generation capacity was evaluated using a lucigenin assay. Histology was performed to examine intracerebral hemorrhage lesion size and location. Results: All animals became hypertensive, and a majority developed intracerebral hemorrhages or died of unknown causes. Baseline blood pressure and responses to the hypertensive stimulus did not differ between groups. Expression of TRPA1 in cerebral arteries from control mice was not altered after 28 days of treatment, but expression of three NOX isoforms and the capacity for ROS generation was increased in hypertensive animals. NOX-dependent activation of TRPA1 channels dilated cerebral arteries from hypertensive animals to a greater extent compared with controls. The number of intracerebral hemorrhage lesions in hypertensive animals did not differ between control and Trpa1-ecKO animals but were significantly smaller in Trpa1-ecKO mice. Morbidity and mortality did not differ between groups. Discussion: We conclude that endothelial cell TRPA1 channel activity increases cerebral blood flow during hypertension resulting in increased extravasation of blood during intracerebral hemorrhage events; however, this effect does not impact overall survival. Our data suggest that blocking TRPA1 channels may not be helpful for treating hypertension-associated hemorrhagic stroke in a clinical setting.

High pulse pressure impairs cerebral artery endothelial function in young, but not old, mice

One of the hallmarks of vascular aging is increased pulse pressure. This elevated pulse pressure is associated with deleterious effects on cerebral vascular function; however, it is unknown if age modulates the susceptibility to high pulse pressure. To examine the effects of age on the cerebral artery response to pulse pressure, we studied isolated cerebral arteries collected from young (6.1 ± 0.2 mo) and old (26.7 ± 0.5 mo) male C57BL/6 mice. Isolated cerebral arteries were exposed ex vivo to static pressure, low pulse pressure (25 mmHg), and high pulse pressure (50 mmHg). In cerebral arteries from young mice, endothelium-dependent dilation was similar between the static and low pulse pressure conditions. Exposure to high pulse pressure impaired endothelium-dependent dilation in cerebral arteries from young mice, mediated by less nitric oxide bioavailability and greater oxidative stress. Cerebral arteries from old mice had impaired cerebral artery endothelium-dependent dilation at static pressure compared with young cerebral arteries. However, exposure to low or high pulse pressure did not cause any further impairments to endothelium-dependent dilation in old cerebral arteries compared with static pressure. The old cerebral arteries had less distension during exposure to high pulse pressure and greater stiffness compared with young cerebral arteries. These results indicate that acute exposure to high pulse pressure impairs endothelium-dependent dilation in young, but not old, cerebral arteries. The greater stiffness of cerebral arteries from old mice potentially protects against the negative consequences of high pulse pressure.

Prenatal exposure to alcohol: mechanisms of cerebral vascular damage and lifelong consequences.

Alcohol is a well-known teratogen, and prenatal alcohol exposure (PAE) leads to a greater incidence of many cardiovascular-related pathologies. Alcohol negatively impacts vasculogenesis and angiogenesis in the developing fetal brain, resulting in fetal alcohol spectrum disorders (FASD). Ample preclinical evidence indicates that the normal reactivity of cerebral resistance arterioles, which regulate blood flow distribution in response to metabolic demand (neurovascular coupling), is impaired by PAE. This impairment of dilation of cerebral arteries may carry implications for the susceptibility of the brain to cerebral ischemic damage well into adulthood. The focus of this review is to consolidate findings from studies examining the influence of PAE on vascular development, give insights into relevant pathological mechanisms at the vascular level, evaluate the risks of ethanol-driven alterations of cerebrovascular reactivity, and revisit different preventive interventions that may have promise in reversing vascular changes in preclinical FASD models.

Hypoxia-related mechanisms inducing acute mountain sickness and migraine.

Experimental models of human diseases are vital for pathophysiological and therapeutic research. To investigate the initiation, maintenance, pathophysiology and even termination of a migraine/headache attack these models are urgently needed. Results from different studies promote the profound involvement of hypoxia in migraine and other primary/secondary headaches. The possible mechanisms that drive the induction of headaches through hypoxia are still unknown, but several modes of action, such as increased blood flow, dilation of cerebral arteries, the release of nitroglycerin, calcitonin gene-related peptide and adenosine or increased oxygen extraction are discussed intensively. In studies exposing healthy volunteers and people with a history of migraine to controlled normobaric hypoxia, our research group could demonstrate normobaric hypoxia to be an effective trigger of migraine headaches. Furthermore, a longitudinal measurement of calcitonin gene-related peptide (CGRP), during a hypoxic challenge in migraine patients, revealed increasing CGRP levels with prolonged hypoxic challenge. Since GRP has been linked to migraine and other headache disorders, hypoxia could be regarded as initiator for headaches on a neurotransmitter basis. Furthermore, it has been known for more than 2 decades from studies in vitro and in vivo that hypoxia can induce cortical spreading depression, a phenomenon believed to represent aura. Considering the increased prevalence of migraine in altitude populations and the solid pathophysiological changes on cellular and neurotransmitter level–the role of hypoxia should be investigated in greater detail by the headache community.

PERMISSIVE ROLE OF ANGIOTENSIN II IN MANTENANCE OF ENDOTHELIUM-DEPENDENT VASODILATION IN CEREBRAL MICROCIRCULATION

Objective: A number of data suggest, rather controversial, permissive role of angiotensin II (ANGII) in maintaining vasodilator responses in microcirculation, via its interaction with AT1 receptors (AT1R). This study aimed to determine the role of ANGII and AT1R in the mechanisms of flow-induced dilation (FID) in middle cerebral arteries (MCA) and incidence of oxidative stress at the functional, cellular and molecular level in the cerebral vasculature and in the serum of Sprague-Dawley (SD) rats fed high salt diet (HS). Design and method: Eleven-week old, male SD rats were randomly assigned to control group (CTRL, 0.4% NaCl in rat chow); Losartan group (rats on a standard diet given the AT1R blocker losartan (1 mg/mL) in drinking water); HS group (7 days 4% NaCl in rat chow) or HS+ANGII group (7 days HS with 3 days ANGII administration via osmotic minipumps (100 ng/kg/min on days 4–7)). FID of MCA was determined in absence/presence of the NOS inhibitor L-NAME, the non-selective cyclooxygenases inhibitor indomethacin, and the superoxide dismutase mimetic TEMPOL. Gene and protein expression of antioxidative enzymes and enzymes involved in FID mechanisms were determined by RT-qPCR and western blot. Vascular NO and superoxide/ROS levels were assessed by direct fluorescence. Serum systemic oxidative stress parameters was measured by spectrophotometry. All experimental procedures conformed to the EU Directive 2010/63/EU. Results: HS or AT1R blockade impaired FID and increased oxidative stress. Supplementation of ANGII restored the mechanisms of FID in MCA of rats fed HS diet to the ones present in CTRL rats without affecting arterial blood pressure by decreasing systemic oxidative stress and decreasing superoxide/ROS levels and increased NO bioavailability in the vascular wall of HS treated rats. The AT1R blockade resulted in significantly attenuated endothelium-dependent dilation, changed mechanisms of FID, increased vascular and systemic oxidative stress and decreased expression/ activity of antioxidative enzymes. Conclusions: ANGII is crucial in the preservation of vascular oxidative stress-antioxidant system balance and via AT1R, in maintenance of physiological vasodilation mechanisms of MCA. Suppression of ANGII is a key link between HS intake and development of endothelial dysfunction, and impaired regulation of cerebral blood flow.

Day to Day Blood Pressure Variability Associated With Cerebral Arterial Dilation and White Matter Hyperintensity.

Background:Previous studies suggested blood pressure variability (BPV) might help reveal interactions between blood pressure fluctuation and white matter lesions, and the impact of elevated BPV on white matter hyperintensity (WMH) or cerebral arterial dilation is unclear.Methods:This retrospective observational study involved 2634 stroke-free individuals (68.6±11.1 years, 50.3% female), who underwent magnetic resonance imaging and magnetic resonance angiography scans, from a single center in Shanghai, China. Measurements for variability of blood pressure were made based on 7 days blood pressure recordings. WMHs were quantified from T2-FLAIR images and further classified as periventricular WMH or deep WMH. M1 segment of middle cerebral artery dilation was assessed from magnetic resonance angiography images. General linear model was used to examine the associations.Results:Both increased systolic and diastolic BPV were associated with increased WMH volume (systolic: β=0.02 [95% CI, 0.004–0.03], P=0.01; diastolic: β=0.05 [95% CI, 0.03–0.08], P<0.001). Only periventricular WMH was associated with BPV (systolic: β=0.02 [95% CI, 0.005–0.04], P=0.01; diastolic: β=0.06 [95% CI, 0.04–0.09], P<0.001). MCA dilation was found in 125 individuals (4.75%). Systolic BPV was associated with MCA dilation only in the hypertensive individuals (β=0.11 [95% CI, 0.06–0.17], P<0.001). Increased WMH volume was found associated with dilated MCA (β=0.17 [95% CI, 0.11–0.23], P<0.001).Conclusions:Increased BPV might be one of the pathophysiological phenomena involving in the small vessel disease independent of hypertension. Increased BPV might independently contribute to intracranial arterial dilation. Management of BPV might be a target to preserve cerebrovascular wellness.

Endothelial Inwardly Rectifying K+ Channel Subunit 2.1 Critically Enables Flow‐mediated Dilation in Cerebral Resistance Arteries

Cerebral blood flow is a highly regulated process tied to the expression of ion channels in endothelial and smooth muscle cells. Of particular note are endothelial inwardly rectifying K+ channels (KIR), membrane proteins that presumably sense hemodynamic stimuli such as blood flow. This study sought to clearly define the role of endothelial KIR2.1 in cerebral arterial blood flow sensing using floxed control and endothelial KIR2.1‐/‐ mice. Experiments progressed from single cell (patch‐clamp electrophysiology of cerebral endothelial and smooth muscle), to isolated vessel (myography of cerebral resistance arteries) and finally to intact organism (arterial spin‐labeling magnetic resonance imaging). Electrophysiological analysis confirmed the presence of KIR activity in endothelial cells from floxed but not endothelial KIR2.1‐/‐ mice; the former was subsequently shown to be flow sensitive. Smooth muscle KIR activity was comparable among the two animal groups. Vessel experiments next revealed that flow‐induced vasodilation was diminished in endothelial KIR2.1‐/‐ mice. In the absence of endothelium, Ba2+‐induced constriction was comparable among the two groups consistent with preserved smooth muscle KIR activity. Intriguingly, the diminishment of cellular and tissue level responses in endothelial KIR2.1‐/‐ mice did not lead to apparent cerebral flow abnormalities (cortex, cerebral nuclei, hippocampus, thalamus, hypothalamus and midbrain), at baseline or following a systemic blood pressure challenge (intraperitoneal phenylephrine). These findings underscore a role for endothelial KIR2.1 activity in hemodynamic sensing, one that is subtle and dynamically balanced with other mechanisms that set cerebral arterial blood flow.

Inflammatory biomarkers are associated with cerebral large artery thickening and dilatation in older adults

AbstractBackgroundAge‐associated changes in intracranial large arteries, including hypertrophic and dilatative remodeling, contribute to worse systemic and brain health in older adults. Vessel wall imaging (VWI) is a novel neuroimaging technique that offers the critical ability to quantify thickness and lumen diameter across arterial segments of the circle of Willis (CoW). Research suggests inflammation, a well‐known feature of aging, cerebrovascular disease, and Alzheimer’s disease, may be a central driver of age‐related changes in CoW morphology. We investigate if fluid biomarkers of inflammation predict key features of intracranial arterial aging, including CoW thickening and dilatation visible on VWI MRI.MethodsVanderbilt Memory &amp; Aging Project participants free of clinical stroke and dementia were studied (n=117, 74±7 years, 73% male). Systemic inflammatory biomarkers (TNF‐α, IL‐6) were quantified from blood plasma samples and neuroinflammatory biomarkers (sTREM2, YKL‐40) were quantified from cerebrospinal fluid samples. Intracranial artery lumen diameter and thickness were manually measured across the basilar artery (BA) and bilateral segments of the internal carotid artery (ICA), anterior cerebral artery (ACA), and middle cerebral artery (MCA) using VWI MRI. Linear regressions related each inflammatory biomarker to intracranial artery lumen diameter and thickness in separate cross‐sectional models, adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile, diagnosis, apolipoprotein ε4 status, and T1‐weighted intracranial volume.ResultsTNF‐α was related to right ICA thickness (b=0.01, p=0.03), left ICA thickness (b=0.01, p&lt;0.05), and left ACA thickness (b=‐0.01, p=0.04); TNF‐α was unrelated to lumen diameters (p&gt;0.51). IL‐6 was related to right ICA thickness (b=0.01, p=0.003) and was unrelated to lumen diameters (p&gt;0.18). sTREM2 was related to left MCA lumen diameter (b=0.0001, p=0.03), right ACA lumen diameter (b=0.0001; p=0.001), and right ACA thickness (b=0.00003, p=0.03). YKL‐40 was unrelated to intracranial artery thickness (p&gt;0.27) and lumen diameter (p&gt;0.05).ConclusionsResults suggest TNF‐α, IL‐6, and sTREM2 are related to intracranial large artery thickening, and sTREM2 may further relate to large artery dilatation. Given the increased reliability of ICA and BA manual measurements on VWI MRI, these findings may be most robust. Proinflammatory cytokines and microglia‐mediated immune responses may be key pathophysiological mechanisms underlying age‐related arterial remodeling within the brain.

Sex Differences in the Relation Between Frailty and Endothelial Dysfunction in Old Mice.

Vascular endothelial function declines with age on average, but there is high variability in the magnitude of this decline within populations. Measurements of frailty, known as frailty index (FI), can be used as surrogates for biological age, but it is unknown if frailty relates to the age-related decline in vascular function. To examine this relation, we studied young (4-9 months) and old (23-32 months) C57BL6 mice of both sexes. We found that FI was greater in old compared with young mice, but did not differ between old male and female mice. Middle cerebral artery (MCA) and mesenteric artery endothelium-dependent dilation (EDD) also did not differ between old male and female mice; however, there were sex differences in the relations between FI and EDD. For the MCA, FI was inversely related to EDD among old female mice, but not old male mice. In contrast, for the mesenteric artery, FI was inversely related to EDD among old male mice, but not old female mice. A higher FI was related to a greater improvement in EDD with the superoxide scavenger 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl in the MCAs for old female mice and in the mesenteric arteries for old male mice. FI related to mesenteric artery gene expression negatively for extracellular superoxide dismutase (Sod3) and positively for interleukin-1β (Il1b). In summary, we found that the relation between frailty and endothelial function is dependent on sex and the artery examined. Arterial oxidative stress and proinflammatory signaling are potential mediators of the relations of frailty and endothelial function.

Lars Edvinsson: bench-to-bedside discovery

Lars Edvinsson: bench-to-bedside discovery

Abstract P163: Acute Treatment With Amyloid Beta Impaired Cerebral Artery Reactivity And Endothelial Sk Channel Activity

Introduction: The accumulation/aggregation of amyloid-beta(Aβ) has been recognized to play a key role in the progression of Alzheimer’s disease (AD) and the neurovascular dysfunction induced by Aβ may contribute to cognitive impairment and dementia during AD. Aβ deposition in cerebrovasculature exerts direct toxicity to smooth muscle cells and impairs nitric oxide signaling in the endothelium. Endothelium-dependent hyperpolarization and vascular relaxation are partially mediated by small-conductance calcium-activated potassium (SK) channels, and the inhibition of SK channels plays an important role in endothelial dysfunction. However, there has been limited investigation into the acute effect of Aβ on the endothelial SK channel function and related cerebrovascular reactivity. Hypothesis: We hypothesized that acute treatment with Aβ downregulates SK channel activity and impaired cerebrovascular reactivity. Methods: Aβ and SK channel activator NS309 were used in measuring in-vitro relaxation response of pre-contracted mouse cerebral arteries, and the SK channel currents of human cerebral artery endothelial cells by the whole-cell patch-clamp. Results: Mouse cerebral artery diameter was no significantly changed in incubation with Aβ (0.5-5μM) for 5 minutes (Fig. A, n=6, respectively). However, cerebral artery dilation with NS309 (10μM) was significantly decreased after incubation with Aβ (1μM) for 2 hours (Fig. B, n=6, respectively). The patch clamp recording showed that total potassium currents were no significantly changed in the incubation with Aβ (0.5-5μM) for 5 minutes (Fig. C&amp;D, n=6, respectively). In contrast, the currents of SK channels in cerebral artery endothelial cells were significantly impaired after incubation with Aβ (1μM) for 2 hours (Fig. E&amp;F, n=5-7, respectively). Conclusions: Acute treatment with Aβ dysregulated of cerebrovascular endothelial SK channels and impaired the cerebrovascular reactivity.

Mechanisms of Increased Infarct Volume in a Rat Model of Ischemic Stroke: Implications for Leptomeningeal Collateral Artery Function and Beta Blocker Therapy

Beta blockers are associated with higher ischemic stroke risk than other anti-hypertensive medications, but the mechanisms of this increased risk remain unknown. We previously reported β1-adrenoceptor-mediated dilation of rat cerebral arteries that is inhibited by the clinical beta blocker metoprolol. The present study examines the effect of β1-adrenoceptor blockade on the leptomeningeal collateral arteries (LCAs). LCAs connect distal branches of middle cerebral arteries to those of posterior and anterior cerebral arteries and provide a path for protective retrograde blood flow to the ischemic tissue during stroke. Pre-treatment with metoprolol increased cerebral infarct volume in Sprague-Dawley rats after middle cerebral artery occlusion (MCAO). Recovery of cortical blood flow after acute MCAO estimated by laser speckle contrast imaging was significantly blunted by topical suffusion of CGP20712, a β1-adrenoceptor antagonist. Isolated LCAs constricted significantly to the mixed adrenoreceptor agonist norepinephrine after pre-treatment with CGP20712 during ex vivo pressure myography. The in vivo diameter response of LCAs or small pial resistance arterioles following MCAO, however, was not significantly altered by topical suffusion of CGP20712. More research is required to fully characterize the effects of beta blockers on cerebral arteries during ischemic stroke.