Cerebral Artery Diameter Research Articles

The effects of Y-27632 on pial microvessels during global brain ischemia and reperfusion in rabbits

BackgroundGlobal brain ischemia-reperfusion during propofol anesthesia provokes persistent cerebral pial constriction. Constriction is likely mediated by Rho-kinase. Cerebral vasoconstriction possibly exacerbates ischemic brain injury. Because Y-27632 is a potent Rho-kinase inhibitor, it should be necessary to evaluate its effects on cerebral pial vessels during ischemia—reperfusion period. We therefore tested the hypotheses that Y-27632 dilates cerebral pial arterioles after the ischemia-reperfusion injury, and evaluated the time-course of cerebral pial arteriolar status after the ischemia-reperfusion.MethodsJapanese white rabbits were anesthetized with propofol, and a closed cranial window inserted over the left hemisphere. Global brain ischemia was produced by clamping the brachiocephalic, left common carotid, and left subclavian arteries for 15 min. Rabbits were assigned to cranial window perfusion with: (1) artificial cerebrospinal fluid (Control group, n = 7); (2) topical infusion of Y-27632 10−6 mol · L−1 for 30 min before the initiation of global brain ischemia (Pre group, n = 7); (3) topical infusion of Y-27632 10−6 mol · L−1 starting 30 min before ischemia and continuing throughout the study period (Continuous group, n = 7); and, (4) topical infusion of Y-27632 10−6 mol · L−1 starting 10 min after the ischemia and continuing until the end of the study (Post group, n = 7). Cerebral pial arterial and venule diameters were recorded 30 min before ischemia, just before arterial clamping, 10 min after clamping, and 5, 10, 20, 40, 60, 80, 100, and 120 min after unclamping.ResultsMean arterial blood pressure and blood glucose concentration increased significantly after global brain ischemia except in the Continuous group. In the Pre and Continuous groups, topical application of Y-27632 produced dilation of large (mean 18–19%) and small (mean; 25–29%) pial arteries, without apparent effect on venules. Compared with the Control and Pre groups, arterioles were significantly dilated during the reperfusion period in the Continuous and Post groups (mean at 120 min: 5–8% in large arterioles and 11–12% in small arterioles).ConclusionsY-27632 dilated cerebral pial arterioles during reperfusion. Y-27632 may enhance recovery from ischemia by preventing arteriolar vasoconstriction during reperfusion.

Morphometric evaluation of the delayed cerebral arteries response to acetazolamide test in patients with chronic carotid artery stenosis using computed tomography angiography.

The evidence accumulates that the response to acetazolamide test is delayed on the ipsilateral side to stenosis. However, the effect of acetazolamide beyond 30 min after acetazolamide administration remains unknown. The aim of this study was to assess the diameters of anterior cerebral arteries (ACAs), middle cerebral arteries (MCAs) and posterior cerebral arteries (PCAs) before and 60 min after the acetazolamide test. Seventeen patients with carotid artery stenosis ≥ 90% on the ipsilateral side and ≤ 50% on the contralateral side were enrolled into the study. Diagnosis was based on ultrasonography examination and was confirmed using digital subtractive angiography. In all patients, two computed tomography angiography examinations were carried out; the first was performed before the acetazolamide administration, while the second one was carried out 60 min after injections. In response to the acetazolamide test: PCA diameter diminished in both ipsi- and contra-lateral side to stenosis (from 1.31 to 1.24 mm and from 1.23 to 1.15 mm, respectively), ACA and MCA decreased in the contralateral side to the stenosis (from 1.33 to 1.26 mm and from 2.75 to 2.66 mm, respectively), ACA and MCA increased in the ipsilateral side to the stenosis (from 1.29 to 1.46 mm and from 2.77 to 2.96 mm, respectively). All changes were statistically significant. There were significant differences in reactivity to acetazolamide challenge between the internal carotid artery (ICA) and vertebrobasilar circulation in patients suffering from chronic carotid artery stenosis. Within the ICA territory, ACA and MCA responses vary in the affected and not affected side.

Abstract 222: Exercise Training Prevents Rarefaction of Pial Collaterals, Promotes Cerebral Arterial Remodeling, and Lessens Severity of Stroke in Aging Brain

Variation in anatomic extent of the collateral circulation is an important determinant of variation in the severity of ischemic stroke and efficacy of revascularization therapies. Yet pial collateral number and lumen diameter decrease with age, at least in mice. It is not known if this can be mitigated. We tested whether exercise training can accomplish this and if it also affects diameter of the posterior communicating collalterals (PComs) and primary cerebral arteries (ICA, BA, MCA, ACA, PCA). We randomized 30 male and 30 female, 12 months-old (~40 human years, hy) C57BL/6J mice to either sedentary or voluntary wheel-running (daily distance run was measured). At 25 mos-age (~70 hy), permanent MCA occlusion was followed 24h later by vascular casting after maximal dilation and by determination of infarct volume. Controls for aging were 3 mos-old sedentary mice (~16 hy). Training effect was confirmed by muscle fiber-type switching, body weight and cardiac hypertrophy (all p<0.05). Exercise prevented age-associated loss of collateral number and diameter (p=0.049 and 0.005, n=13-14) and reduced infarct volume by 50%, ie, to that seen in 3 months-old mice (p=0.01, n=7). Unlike pial collaterals, PCom diameter and number (ie, present bilaterally, unilaterally or absent) were unaffected by exercise. Of further interest, diameter of the primary cerebral arteries increased with aging alone (119 ± 1 vs 134 ± 5 μm averaged combined diameter, p=0.02, n=10-14); this effect tended to increase further with exercise (143 ± 4 μm, p=0.07, n=13). Mechanistically, exercise increased vascular expression (assessed by immunohisto-chemistry) of total eNOS (p=0.03, n=5-6), phospho-eNOS (p=0.004, n=5) and a marker of anti-oxidative stress (SOD, p=0.008, n=5-6; but not HO-1, p=0.40, n=6). It did not alter a marker of aging (p16, p=0.42, n=5); analysis of additional targets is underway. In conclusion, exercise training prevented age-induced rarefaction of pial collaterals and reduced infarct volume. In addition and unexpectedly, aging also caused outward remodeling of the primary cerebral arteries, and exercise training tended to further augment this. These benefits of regular aerobic exercise were associated with increased eNOS bioavailability and reduced oxidative stress.

Distinct mechanisms underlying cholesterol protection against alcohol-induced BK channel inhibition and resulting vasoconstriction

Alcohol (ethanol) at concentrations reached in blood following moderate to heavy drinking (30–80mM) reduces cerebral artery diameter via inhibition of voltage- and calcium-gated potassium channels of large conductance (BK) in cerebral artery smooth muscle. These channels consist of channel-forming α and regulatory β1 subunits. A high-cholesterol diet protects against ethanol-induced constriction via accumulation of cholesterol within the vasculature. The molecular mechanisms of this protection remain unknown. In the present work, we demonstrate that in vitro cholesterol enrichment of rat middle cerebral arteries significantly increased cholesterol within arterial tissues and blunted constriction by 50mM of ethanol. Ethanol-induced BK channel inhibition in inside-out patches excised from freshly isolated cerebral artery myocytes was also abolished by cholesterol enrichment. Enrichment of arteries with enantiomeric cholesterol (ent-cholesterol) also blunted BK channel inhibition and cerebral artery constriction in response to ethanol. The similar protection of cholesterol and ent-cholesterol against ethanol action indicates that this protection does not require protein site(s) that specifically sense natural cholesterol. Cholesterol-driven protection against ethanol-induced BK channel inhibition and vasoconstriction was replicated in myocytes and middle cerebral arteries of C57BL/6 mice. BK β1 subunits are known to regulate vascular diameter and its modification by ethanol. However, blunting of an ethanol effect by in vitro cholesterol enrichment was observed in arteries and myocyte membrane patches from BK β1 (KCNMB1) knockout mice. Thus, BK β1 subunits are not needed for cholesterol protection against ethanol effect on BK channel function and cerebral artery diameter.

Abnormal myosin phosphatase targeting subunit 1 phosphorylation and actin polymerization contribute to impaired myogenic regulation of cerebral arterial diameter in the type 2 diabetic Goto-Kakizaki rat

The myogenic response of cerebral resistance arterial smooth muscle to intraluminal pressure elevation is a key physiological mechanism regulating blood flow to the brain. Rho-associated kinase plays a critical role in the myogenic response by activating Ca2+ sensitization mechanisms: (i) Rho-associated kinase inhibits myosin light chain phosphatase by phosphorylating its targeting subunit myosin phosphatase targeting subunit 1 (at T855), augmenting 20 kDa myosin regulatory light chain (LC20) phosphorylation and force generation; and (ii) Rho-associated kinase stimulates cytoskeletal actin polymerization, enhancing force transmission to the cell membrane. Here, we tested the hypothesis that abnormal Rho-associated kinase-mediated myosin light chain phosphatase regulation underlies the dysfunctional cerebral myogenic response of the Goto-Kakizaki rat model of type 2 diabetes. Basal levels of myogenic tone, LC20, and MYPT1-T855 phosphorylation were elevated and G-actin content was reduced in arteries of pre-diabetic 8–10 weeks Goto-Kakizaki rats with normal serum insulin and glucose levels. Pressure-dependent myogenic constriction, LC20, and myosin phosphatase targeting subunit 1 phosphorylation and actin polymerization were suppressed in both pre-diabetic Goto-Kakizaki and diabetic (18–20 weeks) Goto-Kakizaki rats, whereas RhoA, ROK2, and MYPT1 expression were unaffected. We conclude that abnormal Rho-associated kinase-mediated Ca2+ sensitization contributes to the dysfunctional cerebral myogenic response in the Goto-Kakizaki model of type 2 diabetes.

Magnetic Resonance investigation into the mechanisms involved in the development of high-altitude cerebral edema

Rapid ascent to high altitude commonly results in acute mountain sickness, and on occasion potentially fatal high-altitude cerebral edema. The exact pathophysiological mechanisms behind these syndromes remain to be determined. We report a study in which 12 subjects were exposed to a FiO2 = 0.12 for 22 h and underwent serial magnetic resonance imaging sequences to enable measurement of middle cerebral artery velocity, flow and diameter, and brain parenchymal, cerebrospinal fluid and cerebral venous volumes. Ten subjects completed 22 h and most developed symptoms of acute mountain sickness (mean Lake Louise Score 5.4; p < 0.001 vs. baseline). Cerebral oxygen delivery was maintained by an increase in middle cerebral artery velocity and diameter (first 6 h). There appeared to be venocompression at the level of the small, deep cerebral veins (116 cm3 at 2 h to 97 cm3 at 22 h; p < 0.05). Brain white matter volume increased over the 22-h period (574 ml to 587 ml; p < 0.001) and correlated with cumulative Lake Louise scores at 22 h (p < 0.05). We conclude that cerebral oxygen delivery was maintained by increased arterial inflow and this preceded the development of cerebral edema. Venous outflow restriction appeared to play a contributory role in the formation of cerebral edema, a novel feature that has not been observed previously.

Vascular Contributions to Cognitive Impairment and Dementia: Topical Review of Animal Models.

Cerebrovascular disease and Alzheimer disease (AD) lesions are common in older people and accumulate with age. Cerebrovascular lesions can directly reduce cognitive status: vascular dementia is the second most common cause of clinical dementia after AD. In addition, cerebrovascular lesions worsen the impact of AD and other dementia pathologies and may contribute to AD pathogenesis. This spectrum is reflected in the concept of vascular contributions to cognitive impairment and dementia (VCID).1 There are numerous vascular pathologies underlying VCID.2–4 The most prevalent is cerebral small vessel disease (SVD), or arteriolosclerosis, in small arteries (outer diameter up to ≈200 µm) that supply deep nuclei and deep white matter areas in the human brain.2,3,5,6 Parenchymal lesions associated with SVD vasculopathy are small focal infarcts (lacunes), diffuse white matter lesions (WML), and microhemorrhages.3,4,6 Other VCID-related vascular pathologies include microatheroma, venous collagenosis, and cerebral amyloid angiopathy.1,3,6 The limitations of animal models for VCID are well-known.1,7,8 Experimental species differ from humans in terms of lifespan, relative white matter abundance, large artery dimensions (Figure 1), and in size and morphology of deep penetrating arteries (Figure 2). Nevertheless, animal paradigms provide valuable insights into mechanisms, progression, and possible therapies in VCID. All experimental use of animals for human health-related research carries ethical responsibilities and must be governed by internationally-agreed Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines (http://www.nc3rs.org.uk/arrive-guidelines). Here, we update a previous systematic review of VCID-relevant models8 (online-only Data Supplement) and summarize instructive examples (Table). View this table: Table. Overview of Selected Models Relevant to VCID Figure 1. Lifespan and cerebral large artery diameter, white matter content and blood flow: comparison across species. A , Normal lifespan (open circles) and outer diameter (OD) of …

Rebuttal from Ryan L. Hoiland and Philip N. Ainslie.

Brothers & Zhang (2016) provide a relevant CrossTalk discussion on the measurement of middle cerebral artery (MCA) diameter during alterations in arterial blood pressure (ABP) and gases. While in support of a constant MCA diameter, they nonetheless judiciously acknowledge that several previous studies indicating a constant MCA diameter, specifically during alterations in arterial blood gases, are confounded by subject co-morbidities, anesthesia, and/or suffer from poor resolution (1.5 T MRI) (Schreiber et al. 2000; Serrador et al. 2000). They speculate that elevations in ABP and the associated autoregulatory response concurrent to hypercapnia may explain the increases in diameter reported by the more recent and higher resolution MRI studies (3 and 7 T) assessing MCA diameter (Verbree et al. 2014; Coverdale et al. 2014). The rationale for this hypothesis is unclear as the available data in humans indicate an increase in ABP will increase cerebral vascular resistance in large cerebral arteries (Liu et al. 2013; Warnert et al. 2016). Collectively, these findings indicate that any engagement of autoregulatory mechanisms would more likely lead to an underestimation of vasodilatation, not overestimation. In their discussion of arterial blood gases, Brothers & Zhang fail to discuss the potential for hypoxia-induced vasomotion of the MCA. Previous study has indicated MCA dilatation in hypoxia (Wilson et al. 2011), in addition to more recent evidence that continues to highlight a tendency for increased MCA diameter (Sagoo et al. 2016). Overall there is a strong body of data supporting hypoxia-induced dilatation at the level of the MCA. It is noted by Brothers & Zhang that the study by Serrador et al. (2000) provides insight into MCA diameter during mild hypotension; however, a statistical change in BP did not occur during their simulated orthostasis trial (see Table 2 in Serrador et al. 2000). This renders the study by Giller et al. (1993) the only one to date that has directly imaged MCA diameter during alterations in ABP. Thus, while it remains difficult to definitively conclude the effect of ABP on MCA diameter, a large body of evidence now supports the notion that MCA diameter does change during alterations in arterial blood gases. Although we acknowledge that much utility still exists in the employment of transcranial Doppler ultrasound, we encourage the complimentary addition of multi-modal imaging to provide important new insight into cerebrovascular regulation in humans. Readers are invited to give their views on this and the accompanying CrossTalk articles in this issue by submitting a brief (250 word) comment. Comments may be submitted up to 6 weeks after publication of the article, at which point the discussion will close and the CrossTalk authors will be invited to submit a ‘Last Word’. Please email your comment, including a title and a declaration of interest, to jphysiol@physoc.org. Comments will be moderated and accepted comments will be published online only as ‘supporting information’ to the original debate articles once discussion has closed. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. The authors declare no conflict of interest, financial or otherwise. Both authors have approved the final version of the manuscript and agree to be accountable for all aspects of the work. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.

CrossTalk proposal: The middle cerebral artery diameter does change during alterations in arterial blood gases and blood pressure.

CrossTalk proposal: The middle cerebral artery diameter does change during alterations in arterial blood gases and blood pressure.

CrossTalk opposing view: The middle cerebral artery diameter does not change during alterations in arterial blood gases and blood pressure.

CrossTalk opposing view: The middle cerebral artery diameter does not change during alterations in arterial blood gases and blood pressure.

Abstract 170: Arginase Contributes to Delayed Constriction of Large Cerebral Arteries in a Model of Subarachnoid Hemorrhage

Introduction: Increased arginase activity can limit nitric oxide synthase activity and contribute to age-related increase in aortic stiffness. Hypothesis: Subarachnoid hemorrhage (SAH) produces a delayed increase in arginase activity that contributes to delayed decreases in diameter of major cerebral arteries. Methods: Male rats underwent injection of blood into the cisterna magna on day 0 and again on day 2. Shams had double injection of artificial CSF. Measurements of arginase activity on vessels in the Circle of Willis and pia matter were made with an assay based on the conversion of radiolabeled arginine to urea. Measurements of diameter of basilar, posterior (PCA), middle (MCA), and anterior (ACA) cerebral arteries were made ex vivo after perfusion with paraformaldehyde and black latex casting. Results: Arginase activity (nmol of urea/min/mg of protein) increased from the control value of 13±3 (±SE; n=17) to 24±6 (n=6) at 3 days, 36±14 (n=4) at 5 days, and 48±16 (n=9) at 7 days after SAH and then recovered at 10 days (14±5; n=4) and 14 days (18±6; n=5) after SAH. Infusion of the arginase inhibitor 2(S)-amino-6-boronohexanoic acid (ABH) for 7 days after SAH with an ip osmotic pump blocked the increase in arginase activity (10±2; n=4). Assessment of arterial diameter at 3, 5, 7, 10, and 14 days after SAH revealed the smallest diameters occurring at 7 days (except for MCA which occurred at 5 days). Continuous ip infusion of 10 mg/kg/day ABH significantly attenuated the decrease in diameter (μm) 7 days after SAH in PCA (sham = 249±9, n=8; SAH = 209±12, n=10; SAH+ABH = 255±9, n=6) and ACA (sham = 178±11; SAH = 141±11; SAH+ABH = 198±10). Effects on basilar artery were of marginal significance (P=0.065). Conclusion: SAH produces an increase in vascular arginase activity that is temporally related to delayed decreases in diameter of cerebral arteries. Inhibition of arginase activity prevents the decrease in diameter at 7 days after SAH, thereby indicating a contribution of arginase to delayed arterial constriction/remodeling in post-fixed arteries.

Differential Expression of BK Channel Alpha and Beta1 Subunits in Rat Cerebral Arteries

Large conductance, Ca2+i/voltage-gated K+ channels (BK) regulate several physiological processes (Dopico et al., 2012). Native BK complexes consist of channel-forming α and auxiliary β subunits. Four β subunit types were identified, with β1 being highly expressed in smooth muscle (Brenner et al., 2000). BK β1 modifies the channel response to ligands: it increases the apparent Ca2+ sensitivity, mediates channel activation by cholanes (Brenner et al., 2000; Bukiya et al., 2009) and controls cerebral artery tone modification by selective ligands, including lithocholate (Bukiya et al., 2007; 2013). Here, we studied the expression of BK α and β1 subunits across basilar, anterior, middle and posterior cerebral arteries, and the possible contribution of their expression to channel phenotype and cerebral artery diameter response to lithocholate. Methods included quantitative real-time PCR, confocal microscopy, smooth muscle patch-clamp electrophysiology, and diameter determination of in vitro pressurized cerebral arteries. Results demonstrate: 1) BK α and β1 mRNA transcripts are expressed at higher levels in basilar arteries; 2) BK α protein surface levels in myocyte membranes are similar across the different intracranial territories while β1 levels are higher in basilar artery; 3) BK channel activity is also higher in myocytes from basilar arteries; 4) myocyte BK channels in basilar arteries show the highest response to lithocholate; 5) lithocholate-induced dilation of basilar arteries is significantly higher than those measured in other intracranial territories. Collectively, our results demonstrate differential BK β1 expression, as well as its contribution to BK current phenotype and vasodilation by lithocholate, across the major branches of the Willis’ circle. In particular, basilar arteries seem to be highly sensitive to vasoactive agents that act via BK β1 subunits.Support: HL104631 and AA11560 (AMD), and AHA Predoctoral Fellowship (GK).

Middle cerebral artery diameter changes during rhythmic handgrip exercise in humans

Transcranial Doppler (TCD) sonography is a frequently employed technique for quantifying cerebral blood flow by assuming a constant arterial diameter. Given that exercise increases arterial pressure by sympathetic activation, we hypothesized that exercise might induce a change in the diameter of large cerebral arteries. Middle cerebral artery (MCA) cross-sectional area was assessed in response to handgrip exercise by direct magnetic resonance imaging (MRI) observations. Twenty healthy subjects (11 female) performed three 5 min bouts of rhythmic handgrip exercise at 60% maximum voluntary contraction, alternated with 5 min of rest. High-resolution 7 T MRI scans were acquired perpendicular to the MCA. Two blinded observers manually determined the MCA cross-sectional area. Sufficient image quality was obtained in 101 MCA-scans of 19 subjects (age-range 20–59 years). Mixed effects modelling showed that the MCA cross-sectional area decreased by 2.1 ± 0.8% (p = 0.01) during handgrip, while the heart rate increased by 11 ± 2% (p < 0.001) at constant end-tidal CO2 (p = 0.10). In conclusion, the present study showed a 2% decrease in MCA cross-sectional area during rhythmic handgrip exercise. This further strengthens the current concept of sympathetic control of large cerebral arteries, showing in vivo vasoconstriction during exercise-induced sympathetic activation. Moreover, care must be taken when interpreting TCD exercise studies as diameter constancy cannot be assumed.

Neuronal effects of a nickel-piperazine/NO donor complex in rodents

In the brain, NO is a very important molecule in the regulation of cerebral and extra cerebral cranial blood flow and arterial diameters. It is also importantly involved in many neuronal functions and innumerable roles of NO in many brain related disorders including epilepsy, schizophrenia, drug addiction, anxiety, major depression, have been postulated. The present study aimed to explore the neuronal role exerted by the metal-nonoate compound Ni(PipNONO)Cl, a novel NO donor whose vascular protective effects have been recently demonstrated. Ni(PipNONO)Cl showed antidepressant-like properties in the tail suspension test and antiamnesic activity in the passive avoidance test in the absence of any hypernociceptive response to a mechanical stimulus. These effects were related to the NO-releasing properties of the compound within the central nervous system as demonstrated by the increase of iNOS levels in the brain, spinal cord and dura mater. The modulation of neuronal functions appeared after acute and repeated treatment, showing the lack of any tolerance to neuronal effects. At the dose used (10mg/kg i.p.), Ni(PipNONO)Cl did not induce any visible sign of toxicity and experiments were performed in the absence of locomotor impairments. In addition to the NO-related neuronal activities of Ni(PipNONO)Cl, the decomposition control compound Ni(Pip)Cl2 showed anxiogenic-like and procognitive effects. The present findings showed neuronal modulatory activity of Ni(PipNONO)Cl through a NO-mediated mechanism. The activities of the decomposition compound Ni(Pip)Cl2 attributed to Ni(PipNONO)Cl the capability to modulate additional neuronal functions independently from NO releasing properties extending and improving the therapeutic perspectives of the NO donor.

Effect of endothelin receptor antagonists on clinically relevant outcomes after experimental subarachnoid hemorrhage: a systematic review and meta-analysis.

In clinical trials, endothelin receptor antagonists (ETRAs) reduced vasospasm but did not improve functional outcome after subarachnoid hemorrhage (SAH). We assessed the effects of treatment with ETRAs on clinically relevant outcomes in animal studies modelling SAH by performing a systematic review of the literature for controlled animal studies of ETRAs for the treatment of SAH. Primary outcomes were neurobehavioral outcomes and case fatality. Secondary outcomes were cerebral vasospasm and cerebral blood flow. Summary estimates were calculated using normalized mean difference random effects meta-analysis. We included 27 studies (55 experiments, 639 animals). Neurobehavioral scores were reported in none of the experiments, and case fatality in 8 (15%). Treatment with ETRAs was associated with a pooled odds ratio for case fatality of 0.61 (95% confidence interval (CI), 0.27 to 1.39); a 54% increase (95% CI, 39 to 69) in cerebral arterial diameter; and a 93% increase (95% CI, 58 to 129) in cerebral blood flow. We conclude that there is no evidence from animal studies that treatment with an ETRA improves clinically relevant outcomes after SAH. The reduction in cerebral vasospasm observed in animal studies is consistent with that observed in clinical trials, an effect that is not associated with better functional outcome in patients.

Cerebral angiography, blood flow and vascular reactivity in progressive hypertension

Chronic hypertension alters cerebral vascular morphology, cerebral blood flow (CBF), cerebrovascular reactivity, and increses susceptibility to neurological disorders. This study evaluated: i) the lumen diameters of major cerebral and downstream arteries using magnetic resonance angiography, ii) basal CBF, and iii) cerebrovascular reactivity to hypercapnia of multiple brain regions using arterial-spin-labeling technique in spontaneously hypertensive rats (SHR) at different stages. Comparisons were made with age-matched normotensive Wistar Kyoto (WKY) rats. In 10-week SHR, lumen diameter started to reduce, basal CBF, and hypercapnic CBF response were higher from elevated arterial blood pressure, but there was no evidence of stenosis, compared to age-matched WKY. In 20-week SHR, lumen diameter remained reduced, CBF returned toward normal from vasoconstriction, hypercapnic CBF response reversed and became smaller, but without apparent stenosis. In 40-week SHR, lumen diameter remained reduced and basal CBF further decreased, resulting in larger differences compared to WKY. There was significant stenosis in main supplying cerebral vessels. Hypercapnic CBF response further decreased, with some animals showing negative hypercapnic CBF responses in some brain regions, indicative of compromised cerebrovascular reserve. The territory with negative hypercapnia CBF responses corresponded with the severity of stenosis in arteries that supplied those territories. We also found enlargement of downstream vessels and formation of collateral vessels as compensatory responses to stenosis of upstream vessels. The middle cerebral and azygos arteries were amongst the most susceptible to hypertension-induced changes. Multimodal MRI provides clinically relevant data that might be useful to characterize disease pathogenesis, stage disease progression, and monitor treatment effects in hypertension.

Abstract W MP68: Brain Arterial Diameters and Risk of Vascular Events

Objective: Inward and outward remodeling of cerebral vessels may represent alternate pathological vascular phenotypes. Our aim was to test whether extremes of brain arterial diameters increase risk of death and vascular events. Methods: Cerebral large artery diameters were measured in 1,034 stroke-free participants from Northern Manhattan. Arteries from the Circle of Willis (8) and posterior circulation (5) were measured in regions free of stenosis, adjusted for head size, standardized, and added to create a global measure of diameters in each person. Participants were categorized into the top 5% of the diameter distribution (“outward remodelers”) and bottom 5% (“inward remodelers”), as well as an intermediate referent category (90% of population). We used logistic regression to calculate associations with risk factors and Cox models to calculate risks of outcomes after adjusting for demographic and vascular risk factors. Results: Mean follow-up was 5 ± 2 years. Inward remodelers were more likely to be men (OR 3.3, 95%CI 1.8-6.1) and less likely to be hypertensive (OR 0.5, 95%CI 0.3-0.9) or Hispanic (OR 0.3, 95%CI 0.2-0.6), while outward remodelers were more likely to be women (OR 14.6, 95%CI 3.5-60.5) and Hispanic (OR 8.7, 95%CI 1.2-65.0) compared to participants with less extreme diameters. Inward remodelers had a higher risk of death (HR 1.8, 95%CI 1.1-3.0), vascular death (HR 2.8, 95%CI 1.4-5.7), myocardial infarction (HR 2.5, 95%CI 1.0-6.4) and ischemic stroke (HR 3.4, 95%CI 1.0-10.2). Outward remodelers were not at increased risk of death or vascular events. Compared to those with less extreme diameters, risk of cardioembolic stroke was higher among inward remodelers (11.3 vs. 1.4%, HR 13.9, 95%CI 4.4-44.0) while strokes due to large or small artery disease were more frequent in outward remodelers (3.8 vs 1.8 %, HR 3.4, 95%CI 0.7-16.3). Conclusions: Individuals with the smallest brain arterial diameters are at greater risk of death, myocardial infarction, and ischemic stroke, while those with the largest brain arterial diameters were not. Cerebral arterial phenotypes might identify people at greater risk of cardiac disease and stroke, and direct targeting of primary preventive measures at likely stroke subtypes.

Abstract T P94: Differential Response to Treatment of Stroke in Rats With T1dm With Bone Marrow Stromal Cells Derived From Normal or T1DM Rats

Objective: Treatment of stroke with bone-marrow-stromal cells (BMSCs) derived from normal rats (Nor-BMSCs) at 24h after stroke onset improves functional recovery in non-DM rats, but not in type-one DM (T1DM) rats. In the present study, we tested the differential therapeutic effects and mechanisms of action of the treatment of T1DM stroke with BMSCs derived from DM rats (DM-BMSCs) or Nor-BMSCs. Methods: T1DM rats were subjected to 2h of middle cerebral artery occlusion (MCAo) and were treated with DM-BMSCs, Nor-BMSCs or vehicle control (n=8/group) initiated at 24h after MCAo. A battery of functional tests, and vascular and white matter (WM) changes and in vitro cell culture experiments were performed. Results: Compared with Nor-BMSCs, treatment of stroke in T1DM rats with DM-BMSCs significantly improved functional outcome. DM-BMSCs increased vascular remodeling identified by cerebral vascular density and cerebral artery density, increased Bielschowsky silver (axon marker) and Luxol fast blue (myelin marker) expression in the ischemic border zone (IBZ) compared to T1DM-MCAo rats (p&lt;0.05). However, DM-BMSC treatment also increased artherosclerosis-like changes identified by an increased internal carotid wall thickness, artery intimae thickness, and decreased cerebral artery diameter (p&lt;0.05) compared to T1DM-MCAo control. DM-BMSCs treatment significantly increased PDGF, but decreased RhoA and ROCK expression in the IBZ. In vitro, DM-BMSCs have higher miR133b (1.9 fold) expression compared to Nor-BMSCs. DM-BMSC conditioned medium increased brain endothelial cell, smooth muscle cell and oligodendrocyte progenitor cell survival, as well as increased subventricular zone explant cell migration and primary cortical neuron axon outgrowth compared to Nor-BMSC conditioned or control medium. Conclusion: Treatment of stroke in T1-DM rats with DM-BMSCs have dual effects on stroke, i.e. significantly increases neurovascular remodeling, improves neurological recovery, and induces artherosclerosis-like vascular changes. The miR133b/RhoA/ROCK pathway may play a role in the DM-BMSC induced neurorestorative effects.

Abnormal Rho-associated kinase activity contributes to the dysfunctional myogenic response of cerebral arteries in type 2 diabetes.

The structural and functional integrity of the brain, and therefore, cognition, are critically dependent on the appropriate control of blood flow within the cerebral circulation. Inadequate flow leads to ischemia, whereas excessive flow causes small vessel rupture and (or) blood-brain-barrier disruption. Cerebral blood flow is controlled through the interplay of several physiological mechanisms that regulate the contractile state of vascular smooth muscle cells (VSMCs) within the walls of cerebral resistance arteries and arterioles. The myogenic response of cerebral VSMCs is a key mechanism that is responsible for maintaining constant blood flow during variations in systemic pressure, i.e., flow autoregulation. Inappropriate myogenic control of cerebral blood flow is associated with, and prognostic of, neurological deterioration and poor outcome in patients with several conditions, including type 2 diabetes. Here, we review recent advances in our understanding of the role of inappropriate Rho-associated kinase activity as a cause of impaired myogenic regulation of cerebral arterial diameter in type 2 diabetes.

Angiographic Morphometry of Internal Carotid Artery Circulation in Turkish Children.

Knowledge of cerebrovascular morphology is integral in planning neuroendovascular interventions, especially for procedures involving placement of stents, flow diverters or stentrievers. There is insufficient data on angiographic normative values of cerebral circulation in the pediatric age group since angiograms are uncommonly performed in children except for arteriovenous malformations in which arterial dimensions are larger than normal. We aimed to measure the diameters of internal carotid circulation (ICC) arteries on digital subtraction angiograms of pediatric patients and determine the growth trends. This is a retrospective cross-sectional study measurements of ICC arteries of 64 pediatric patients (4-122 months) with retinoblastoma undergoing intra-arterial chemotherapy. Petrous, cavernous, supraclinoid and choroidal segments of internal carotid artery (ICA) and anterior cerebral artery (ACA) diameters had significant correlation with age. Most of the growth was noted in the first 36-48 months of life. Middle cerebral artery (MCA) diameter did not show significant correlation with age. 87% of the adult diameter of the MCA was attained in the first 6 months of life. ICC arteries reached 81% to 99% of adult sizes in the first 48 months of life. On the contrary, the main iliac artery was only 59% of the adult diameter at this age group. Use of current intracranial stents in children appears tolerable due to the growth pattern of ICC arteries. Based on this data, the current armamentarium of intracranial stents or stent-like devices is sufficient to cover the need in the pediatric population.