Cerebral Microvascular Function Research Articles

Super-Resolution Ultrasound Reveals Cerebrovascular Impairment in a Mouse Model of Alzheimer's Disease.

Increasing evidence has suggested a link between cerebrovascular disease and the cognitive impairment associated with Alzheimer's disease. However, detailed descriptions of microvascular changes across brain regions and how they relate to other more traditional pathology have been lacking. Additionally, the efforts to elucidate the interplay between cerebral microvascular function and Alzheimer's disease progression are complicated by the necessity of probing deep-brain structures since early-stage Alzheimer's disease typically involves hippocampal pathology. The purpose of this study was to examine changes in microvascular dynamics in a mouse model of Alzheimer's disease using cohorts that were age-matched to wild-type controls. Data from both sexes were included in this study. Super-resolution ultrasound localization microscopy revealed microvascular functional and structural features throughout the whole brain depth to visualize and quantify. We found that functional decreases in hippocampal and entorhinal flow velocity preceded structural derangements in regional vascular density. Co-registered histological sectioning confirmed the regionalized perfusion deficits seen on ultrasound imaging, which were co-localized with amyloid beta plaque deposition. In addition to providing global vascular quantifications of deep brain structures with a high local resolution, this technology also permitted velocity-profile analysis of individual vessels and, in some cases, allowed for decoupling of arterial and venous flow contributions. These data suggest that microvascular pathology is an early and pervasive feature of Alzheimer's disease and may represent a novel therapeutic target for this disease.

Shexiang Tongxin dropping pills protect against ischemic stroke-induced cerebral microvascular dysfunction via suppressing TXNIP/NLRP3 signaling pathway

Ethnopharmacological relevancePatients with ischemic stroke (IS) often continue to exhibit cerebral microcirculatory dysfunction even after receiving thrombolytic therapy. Enhancing the function of cerebral microvascular endothelia represents a pivotal advancement in the therapeutic strategy for ischemic microcirculatory disturbances. A traditional Chinese medicinal formulation named Shexiang Tongxin Dropping Pills (STDP), has been clinically employed to ameliorate microcirculatory abnormalities. Existing literature attests to the beneficial role of STDP on endothelial cells (ECs). Nevertheless, specific impacts and underlying mechanisms of STDP in rectifying IS-induced cerebral microvascular dysfunction warrant further exploration. Aim of the studyThis investigation seeks to delineate the effects of STDP on cerebral microvascular endothelial damage induced by ischemic stroke and to elucidate the underlying mechanism involved. Materials and methodsMiddle cerebral artery occlusion and reperfusion (MCAO/R) technique was employed to established ischemic stroke model in mice. The therapeutic efficacy of STDP on cerebral microvascular function was assessed through laser speckle contrast imaging, behavioral assays, and histological evaluations. Biochemical markers in the brain tissue, including GSH, SOD, MDA, and ROS, were quantified using specific assay kits. In vitro study, oxygen-glucose deprivation and reperfusion (OGD/R) was performed in bEnd.3 cells. The cytoprotective potential of STDP was then evaluated by measuring cell viability, LDH activity, endothelial permeability, and oxidative stress parameters. Important targets in critical pathway were verified by immunoblotting and immunofluorescence both in mice brain slices and bEnd.3 cells. ResultsSTDP decrease brain infarct size, repaired microvascular cerebral blood flow and attenuated neurological deficiency in MCAO/R mice. Moreover, STDP abolished MCAO/R-induced oxidative stress which was reflected by rescuing GSH content, restoration of SOD activity and T-AOC, reduction of MDA and ROS. Ex vivo, STDP increased cerebral microvascular endothelial cells viability, abolished oxidative stress and decreased their permeability after ODG/R. Mechanistically, STDP significantly suppressed endothelial ROS-TXNIP mediated the activation of NLRP3 inflammasome in vivo and in vitro. ConclusionSTDP improves ischemic stroke-induced cerebral microcirculatory deficits by regulating cerebral microvascular endothelial ROS/TXNIP/NLRP3 signaling pathway.

Effects of candesartan on cerebral microvascular function in mild cognitive impairment: Results of two clinical trials.

Cerebral microvascular dysfunction is commonly seen in Alzheimer's disease (AD) and vascular cognitive impairment (VCI). Cerebrovascular reactivity (CVR) to CO2 reflects cerebral microvascular health and may be modulated by the renin-angiotensin system (RAS). This study aimed to investigate the effects of RAS modulation on CVR in individuals with mild cognitive impairment (MCI) due to underlying vascular or AD etiologies. This study presents findings of candesartan's effects on the secondary outcomes of two double-blind randomized clinical trials of 12-month therapy of candesartan versus lisinopril in VCI (CALIBREX (Candesartan vs Lisinopril Effects on the Brain and Endothelial Function in Executive MCI)) and candesartan versus placebo in prodromal AD (Candesartan's Effects on Alzheimer's Disease and Related Biomarkers (CEDAR)). Primary outcome results of these trials have been reported in previous publications. Participants underwent identical brain blood oxygenation level dependent (BOLD)-CVR in response to a 2-min CO2 challenge at baseline and 12 months. Regions of interest and voxel-wise CVR maps were derived from BOLD signal changes during CO2 challenge. CVR effects were compared between candesartan and lisinopril (CALIBREX) and candesartan and placebo (CEDAR) using mixed-model repeated measures. Data from 102 participants in the CALIBREX study (mean age = 65 years, 45% female, 63% African American) and 59 in the CEDAR study (mean age = 67 years, 32% female, 20% African American) were analyzed. Candesartan was associated with improved whole brain CVR compared to placebo in the CEDAR study (adjusted within-group mean difference for candesartan = 0.27 (95% confidence interval (CI) = 0.006, 0.53) vs placebo = -0.17 (95% CI = 0.42, 0.08), p-value = 0.018), and compared to lisinopril in the CALIBREX study (adjusted within-group mean difference for candesartan = 0.28 (95% CI = 0.10, 0.46) vs lisinopril = -0.08 (95% CI = -0.31, 0.14), p-value = 0.012), independent of blood pressure. In an exploratory meta-analysis of the two trials, improved CVR in the hippocampus was linked to improved attention and working memory (p = 0.044) and a trend for improved executive function (p = 0.087) with candesartan therapy. This study suggests that candesartan is associated with improved microvascular function in MCI, and these findings are independent of its blood pressure effect in these VCI and prodromal AD populations.

Liuwei Dihuang Pills in the Treatment of Senile Dementia: A Review

Objective To elucidate the synergistic mechanism of Liuwei Dihuang Pills (LWDHP), with multi-components, multi-targets and multi-channels in the treatment of senile dementia. Methods We searched Chinese and English databases to obtain the blood components of LWDHP, its clinical and preclinical mechanism research progress in the treatment of senile dementia. Based on the network pharmacology of the key pathophysiological process of Alzheimer’s disease (AD), we screened the anti-AD target of LWDHP and its blood components. Results The therapeutic effect of LWDHP on senile dementia is accurate, with few adverse reactions. Its mechanism includes regulation of cholinergic system, autophagy, cerebral microvascular function, neuron apoptosis, insulin signal transduction pathway, etc. In this review, 35 blood components of LWDHP based on HPLC were collected, and their drug toxicity and safety were evaluated. The network pharmacology analysis based on the pathophysiological process of AD shows that the key components of LWDHP in the treatment of AD are Alisol A monoacetate, Linoleic acid, Alisol F, Tumulosic acid, Methyl eugenol, Palmitic acid and Pachymic acid. Conclusion This article summarizes 35 blood components of LWDHP, summarizes the synergistic mechanism of LWDHP in the treatment of senile dementia, uses network pharmacology to provide a series of potential lead compounds for the development of senile dementia’s drugs, and provides a theoretical basis for further expanding the clinical application of LWDHP.

PS-B10-6: CAPILLARY-TO-ARTERIOLAR SIGNALLING, INFLAMMATION AND SMALL VESSEL DISEASE OF THE BRAIN

Objective: Chronic cerebral inflammation is thought to be a mechanism by which hypertension causes small vessel disease of the brain, leading to dementia. Mouse studies have demonstrated enhanced small resistance artery constriction and neurovascular uncoupling in hypertension. We wished to examine whether acute exposure to the predominant inflammatory driver in hypertension, interleukin-1β; (IL-1β;) could account for this dual vascular deficit. Design and method: Pressure myography of freshly isolated mouse posterior cerebellar pial arteries was used to assess contributions of the inwardly rectifying K+ 2.1 (KIR2.1) channel to vasodilation. In order to assess neurovascular coupling from a vascular perspective, we adopted a recently described approach: the Capillary to Parenchymal Arteriole (CaPA) preparation. In the CaPA preparation, penetrating arterioles (< 40ums) with attached capillary branches are isolated and pressurised. The capillary branch and arteriole are independently stimulated via a micropipette and arteriole diameter is recorded. This approach enables the retrograde hyperpolarising signal from the KIR2.1 channel, which propagates against the flow of blood in the brain, to be assessed both in terms of the extent of arteriole vasodilation and the speed of communication (video). In order to assess the effects of perivascular inflammation on cerebrovascular function, we incubated (in culture medium) small pial arteries with IL-1β; for 24 hours prior to study on a pressure myograph rig. KIR2.1 function was assessed using 10 mM exogenous K+. Cerebral arterioles with attached capillaries were incubated with IL-1β; for 2 hours prior to CaPA study. We then examined the capillary-to-arteriolar signalling mechanism via application of 10 mM K+ to the capillary. We also assessed arteriolar tone and reaction to directly applied K+, NS309 and U46619. Results: Preliminary data suggests that sub-acute incubation with exogenous IL-1β; had no effects on the degree of pressure induced constriction of either the pial artery or the arteriole. CaPA preparation showed that the KIR2.1 capillary-to-arteriolar signalling was preserved as well as arteriolar responses to direct K+, NS309 and U46619 following IL-1β; exposure. Conclusions: Whilst chronic cerebral inflammation in the setting of hypertension results in cerebrovascular deficits, sub-acute exposure with IL-1β; does not appear to significantly impair cerebral microvascular function. Precisely how chronic exposure to inflammation in hypertension induces neurovascular uncoupling is the subject of ongoing investigation.

Association of Cerebrovascular Reactivity and Cognitive Performance in a Racially Diverse Cohort

AbstractBackgroundCerebrovascular reactivity (CVR) to increased carbon dioxide (CO2) reflects cerebral microvascular function and is impaired in hypertension and stroke. Limited studies have looked at its relationship with cognitive performance in African Americans and Whites.MethodsWe used data from the Brain‐Stress Hypertension and Aging Program cohort (B‐SHARP) consisting of racially diverse individuals with normal cognition or mild cognitive impairment (MCI). CVR was measured using advanced signal modeling approach developed by BH/IH during blood oxygenation level dependent (BOLD) resting state ‐fMRI. Participants underwent cognitive assessment using global and domain‐specific tests such as Montreal Cognitive Assessment (MoCA), Boston Naming Test (BNT), Hopkins Verbal Learning Test‐Revised (HVLT‐R), and Trail Making Test. We used multivariate regression models to assess the relationship of CVR and cognitive domains and tested interaction of CVR with race.ResultsSuccessful CVR data were completed on 219 participants with mean age= 65.3 years (SD 7.8), 46% African American and 65% women. An increased resting whole brain CVR was associated with a higher MoCA score (β = 6.46, SE 2.43, p‐value 0.008), higher BNT score (β =2.15, SE 0.93 p‐value 0.02), and shorter time on Trail B‐A, (β= ‐113.4, SE 42.0, p‐value 0.007) after adjusting for mean arterial pressure. After adjusting for age, sex, and race, increased resting whole brain CVR was associated with higher MoCA (β =4.4, SE 2.26, p‐value 0.05), BNT score (β =1.46, SE 0.89, p‐value 0.1) and Trail B‐A score (β =‐86.7, SE 40.3, p‐value 0.03). There was no association with delayed memory based on HVLT‐R. The results were similar for individuals with normal cognition or MCI. There was a significant interaction by race (p<0.01) such that whole brain CVR was associated with better performance on all cognitive tests for African Americans but not for Whites.ConclusionsHigher CVR, reflected by resting state BOLD‐fMRI, was associated with higher overall cognitive status and specific domains including language and executive functioning in individuals with normal cognition or MCI. The differential effect in African Americans vs Whites could suggest a greater contribution of microvascular dysfunction for the higher prevalence of cognitive impairment in African Americans.

Cognitive impairment and microvascular function in end-stage renal disease.

ObjectiveHemodialysis patients show an approximately threefold higher prevalence of cognitive impairment compared to the age‐matched general population. Impaired microcirculatory function is one of the assumed causes. Dynamic retinal vessel analysis is a quantitative method for measuring neurovascular coupling and microvascular endothelial function. We hypothesize that cognitive impairment is associated with altered microcirculation of retinal vessels.Methods152 chronic hemodialysis patients underwent cognitive testing using the Montreal Cognitive Assessment. Retinal microcirculation was assessed by Dynamic Retinal Vessel Analysis, which carries out an examination recording retinal vessels' reaction to a flicker light stimulus under standardized conditions.ResultsIn unadjusted as well as in adjusted linear regression analyses a significant association between the visuospatial executive function domain score of the Montreal Cognitive Assessment and the maximum arteriolar dilation as response of retinal arterioles to the flicker light stimulation was obtained.ConclusionThis is the first study determining retinal microvascular function as surrogate for cerebral microvascular function and cognition in hemodialysis patients. The relationship between impairment in executive function and reduced arteriolar reaction to flicker light stimulation supports the involvement of cerebral small vessel disease as contributing factor for the development of cognitive impairment in this patient population and might be a target for noninvasive disease monitoring and therapeutic intervention.

Mechanisms Underlying the Altered Bioenergetics of Aged Brain Microvasculature

Objective Aging impairs the cerebral microvascular function leading to increased risk of stroke and cognitive decline. The objective of this study was to identify the mechanisms underlying the aging-induced alterations in cellular energetics of brain microvessels (BMVs). Methods BMVs were isolated from young (2-4 months) and aged (24 months) male mice (C57Bl/6) using a combination of filters with pore sizes of 300μm and 40μm followed by gradient centrifugation. Extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) were measured from real time ATP rate assay utilizing Seahorse XFe24 analyzer. Subsequently, total ATP production rate, GlycoATP and MitoATP levels were calculated. Mitochondrial fuel dependency of BMVs was assayed. Immunoblotting measured the protein levels of glucose transporter 1 (GLUT1), carnitine palmitoyltransferases (CPTs), 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PKKFB3), and ETC complexes (ETCs). Enzyme assays measured the activity of lactate dehydrogenase (LDH), citrate synthase (CS), and glutamate dehydrogenase (GDH). Results We found that oxidative phosphorylation (OxPhos) is the major contributor of cellular energy in the BMVs instead of glycolysis (67.0±2.1% vs 32.9±2.1%, n=7-10 mice/age group). Aged BMVs exhibited decreased total ATP production (49.7%, 8.8±2.0 vs 17.6±6.7 pico moles of ATP/µg/min, p=0.004, n=7-10 mice/age group). ATP generation from the glycolysis was more diminished in aged BMVs (74.7%, 1.5±0.3 vs 5.9±1.1 pico moles of ATP/µg/min, p=0.004, n=7-10 mice/group) than OxPhos (55.6%, 5.2±0.53 vs 11.7±1.8 pico moles of ATP/µg/min, p=0.01, n=7-10mice/group) when compared with young BMVs. GLUT1 levels were decreased in the aged BMVs when compared with the young BMVs (32%, 0.19±0.01 vs 0.28±0.02 A.U., p=0.01, n=12 mice/group). Glycolysis-stimulating enzyme, PFKFB3 expression was diminished (51.4%, 0.69±0.08 vs 1.42±0.13 A.U., n=6 mice/group) in the aged BMVs. Neither CPT nor ETC protein levels were affected by aging. Activity of Krebs cycle enzyme, CS, was reduced in the aged versus young BMVs (25.7%, 74.3±6.1% vs 100.0±9.9% nanomoles of substrate/min/mg, p=0.04, n=11-12 mice/group). Although relative utilizations of glucose and fatty acids were not affected by aging, glutamine utilization was enhanced in aged BMVs compared to young BMVs which was accompanied by increased activity of GDH, an enzyme involved in the mobilization of glutamine through Krebs cycle (24.7%, 116.8±4.3% vs 93.6±7.3% pico moles of NADH/min/mg, p=0.01, n=11-12 mice/group). Conclusions The results suggest that 1). diminished energy production in the aged BMVs is related to impaired glycolysis and OxPhos, and 2). multiple defects involving the expression of proteins and activity of enzymes related to glycolysis, OxPhos, and energy substrate utilization mediate the aging-induced impaired microvascular bioenergetics.

Continuous theta burst stimulation provides neuroprotection by accelerating local cerebral blood flow and inhibiting inflammation in a mouse model of acute ischemic stroke

Acute ischemic stroke is a leading cause of disability with limited therapeutic options. Continuous theta burst stimulation (cTBS) has recently been shown to be a promising noninvasive therapeutic strategy for neuroprotection in ischemic stroke patients. Here, we investigated the protective effects of cTBS following acute infarction using a photothrombotic stroke (PTS) model in the right posterior parietal cortex (PPC) of C57BL/6 mice. Treatment with cTBS resulted in a reduction in the volume of the infarct region and significantly increased vascular diameter and blood flow velocity in peri-infarct region, as well as decreased the numbers of calcium binding adapter molecule 1 (Iba-1)-positive microglia and glial fibrillary acidic protein (GFAP)-positive astrocytes. Moreover, the number of CD16/32 positive microglia was decreased, whereas the number of CD206 positive microglia was increased. In addition, performance in a water maze task was significantly improved. These results indicated that cTBS protected against PPC infarct region, leading to an improvement in spatial cognitive function, possibly as a result of changes to cerebral microvascular function and inflammatory responses.

Insulin‐induced hypoglycemia directly affects the cerebral microvasculature in vivo

ObjectiveInsulin therapy for patients with diabetes mellitus (DM) carries the risk for acute hypoglycemia (HG). Evidence from human and animal studies has suggested a role for HG in the exacerbation of cardiovascular dysfunction accompanying DM. Specifically, animal studies have shown that recurrent HG promotes increased ischemic brain injury. Furthermore, HG has been shown to affect mitochondrial function in cultured endothelial cells. Therefore, we hypothesized that acute insulin‐induced HG directly affects the cerebral microvascular function in vivo.MethodsWild type C57Bl/6 mice were prepared for long term two‐photon microscopy by removing a 4mm diameter section of bone over the somatosensory cortex which was then sealed with a glass coverslip held in place with cyanoacrylate and dental acrylic. A custom titanium bar was added to the preparation for head fixation during imaging. During imaging sessions, the cerebral vasculature was visualized using FITC‐dextran 40kDa. Mice were imaged under hypoglycemia (63.2 +/− 8.2 mg/dL by imaging start) using 1–2 U/kg of Humulin‐R. Microvessels approximately 3–5μm in diameter were measured for diameter changes using ImageJ. Blood flow through cerebral microvessels was assayed using line scans over the vasculature to determine red blood cell (RBC) traffic and speed. Fluorescence intensity was also measured in ImageJ to determine any changes in BBB permeability.ResultsAcute hypoglycemia induces a vasodilatory effect in cerebral microvasculature (diameter increased by 10.0 +/− 1.7 %, N=7 mice, n=89 microvessels, vs. 1.751 +/− 1.0 % N=6 mice, n=134 microvessels, in saline controls, p = .0007). However, blood flow was not changed between groups (149.0 +/− 7.4 vs. 167.6 +/− 11.3 RBC/sec and 0.979 +/− 0.060 vs. 1.052 +/− 0.068 μm/ms). Additionally, acute hypoglycemia caused no noticeable changes in the permeability of the BBB indicated by the extravasation of FITC‐dextran.ConclusionsOur data show that acute HG causes noticeable changes in the in vivo cerebral microvasculature, however, we did not note any changes in blood flow, potentially due to cerebral auto regulation. We therefore conclude that insulin‐induced HG causes noticeable direct effects on the cerebral vasculature that may play a role in cerebro vascular impairments in DM.Support or Funding InformationNational Institute of Health: National Institute of General Medical Sciences, National Institute of Aging, and National Institute of Neurological Disorders and Stroke (Mostany: R01AG049821; Katakam: R01NS094834).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Cyclooxygenase Inhibition and Cerebrovascular Reactivity: Interaction of Aging and Aerobic Fitness

The ability of the cerebral microvessels to respond to chemical or metabolic stimuli declines with age and this change may be one mechanism through which age‐related cognitive decline occurs. Prostaglandins play an important role in the control of vascular tone, therefore changes in prostaglandin synthesis or expression may be underlying the age‐related alterations in cerebral microvascular function. Additionally, we have previously shown that aerobic fitness was associated with a decrease in cerebral microvascular function after cyclooxygenase (COX) blockade; yet this was in a small sample size of healthy older adults who were not exercise trained. Thus, the purpose of our study was to evaluate the effect of age on cerebral microvascular reactivity to hypercapnia (CVR) and to determine if habitual exercise modifies the response to COX blockade. We recruited 45 younger (YA; age = 26±1 y) and 31 older (OA; age = 63±1 y) healthy adults, including 21 sedentary YA, 24 exercising YA, 12 sedentary OA, and 19 exercising OA. Aerobic fitness (VO2 max) was measured during an incremental cycle ergometer test. Middle cerebral artery blood flow velocity (MCAv) and end‐tidal CO2 (ETCO2) were continuously recorded. CVR was calculated as the linear slope of the relationship between ETCO2 and MCAv and was assessed before and after the administration of the COX inhibitor indomethacin (INDO). The change in CVR was calculated as pre INDO CVR – post INDO CVR. There were no group differences in MCAv pre INDO (YA: 65±3 cm/s vs. OA: 59±3 cm/s; p>0.05); however, YA had higher MCAv post INDO (YA: 45±1 cm/s vs. OA: 40±2 cm/s; p<0.05). OA had significantly greater change in CVR compared with YA (2.0±0.1 cm/s/mmHg vs. 1.5±0.2 cm/s/mmHg, respectively; p<0.05). There was also a significant effect of habitual exercise, such that sedentary adults had a greater change in CVR compared with exercising adults (2.0±0.2 cm/s/mmHg vs. 1.5±0.2 cm/s/mmHg, respectively; p<0.05). In addition, there was an inverse association between VO2 max and the change in CVR in OA (r=0.42, p<0.05), but not in YA (p>0.05). Our results indicate that older adults, regardless of exercise status, rely more on COX‐derived products for cerebral microvascular responses to hypercapnia. Our results also suggest that habitual exercise may alter the contribution of COX‐derived products to cerebral blood flow regulation.Support or Funding InformationSupported by National Institute of Health grant HL118154This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Cerebral microvascular dysfunction in metabolic syndrome is exacerbated by ischemia\u2013reperfusion injury

BackgroundMetabolic syndrome (MetS) is associated with an increased risk of cerebrovascular diseases, including cerebral ischemia. Microvascular dysfunction is an important feature underlying the pathophysiology of cerebrovascular diseases. In this study, we aimed to investigate the impacts of ischemia and reperfusion (IR) injury on the cerebral microvascular function of rats with high-fat diet-induced MetS.ResultsWe examined Wistar rats fed a high-fat diet (HFD) or normal diet (CTL) for 20 weeks underwent 30 min of bilateral carotid artery occlusion followed by 1 h of reperfusion (IR) or sham surgery. Microvascular blood flow was evaluated on the parietal cortex surface through a cranial window by laser speckle contrast imaging, functional capillary density, endothelial function and endothelial–leukocyte interactions by intravital videomicroscopy. Lipid peroxidation was assessed by TBARs analysis, the expression of oxidative enzymes and inflammatory markers in the brain tissue was analyzed by real-time PCR. The cerebral IR in MetS animals induced a functional capillary rarefaction (HFD IR 117 ± 17 vs. CTL IR 224 ± 35 capillary/mm2; p < 0.05), blunted the endothelial response to acetylcholine (HFD IR −16.93% vs. CTL IR 16.19% from baseline inner diameter p < 0.05) and increased the endothelial–leukocyte interactions in the venules in the brain. The impact of ischemia on the cerebral microvascular blood flow was worsened in MetS animals, with a marked reduction of cerebral blood flow, exposing brain tissue to a higher state of hypoxia.ConclusionsOur results demonstrate that during ischemia and reperfusion, animals with MetS are more susceptible to alterations in the cerebral microcirculation involving endothelial dysfunction and oxidative stress events.

Cerebral Vascular Injury in Traumatic Brain Injury

Traumatic cerebral vascular injury (TCVI) is a very frequent, if not universal, feature after traumatic brain injury (TBI). It is likely responsible, at least in part, for functional deficits and TBI-related chronic disability. Because there are multiple pharmacologic and non-pharmacologic therapies that promote vascular health, TCVI is an attractive target for therapeutic intervention after TBI. The cerebral microvasculature is a component of the neurovascular unit (NVU) coupling neuronal metabolism with local cerebral blood flow. The NVU participates in the pathogenesis of TBI, either directly from physical trauma or as part of the cascade of secondary injury that occurs after TBI. Pathologically, there is extensive cerebral microvascular injury in humans and experimental animal, identified with either conventional light microscopy or ultrastructural examination. It is seen in acute and chronic TBI, and even described in chronic traumatic encephalopathy (CTE). Non-invasive, physiologic measures of cerebral microvascular function show dysfunction after TBI in humans and experimental animal models of TBI. These include imaging sequences (MRI-ASL), Transcranial Doppler (TCD), and Near InfraRed Spectroscopy (NIRS). Understanding the pathophysiology of TCVI, a relatively under-studied component of TBI, has promise for the development of novel therapies for TBI.

Mild deoxycorticosterone (DOCA)/salt‐induced hypertension causes cerebral microvascular dysfunction via a rho kinase dependent mechanism (1070.4)

Hypertension is a major cause of cerebrovascular disease. Microvascular dysfunction in brain is a key feature of small vessel disease that increases the risk of stroke and cognitive impairment. We tested whether mild DOCA/salt‐induced hypertension alters cerebral microvascular function. We treated male C57Bl6 mice with DOCA and 0.9% salt in their drinking water for 3 weeks and measured microvascular reactivity in anesthetized mice using a cranial window preparation. Blood pressure was elevated after DOCA/salt treatment (79±2 vs 95±3 mmHg; P&lt;0.01). Endothelium‐dependent dilation of small cerebral arterioles was selectively impaired in mice treated with DOCA/salt compared with sham (eg, 10 μM acetylcholine: 29±5% vs 11±2%; P&lt;0.01). Endothelium‐independent vasodilation to nitroprusside (an NO donor) or nifedipine (a Ca2+ channel blocker) was similar between groups. Rho kinase is a potential mediator of cerebrovascular disease. Local inhibition of Rho kinase with Y27632 did not affect endothelium‐dependent dilation in sham. In contrast, Y27632 restored endothelium‐dependent dilation to normal in DOCA/salt mice (3 µM) (10 μM acetylcholine: 10±1% vs 22±4%; P&lt;0.01). These findings demonstrate that mild DOCA/salt‐induced hypertension profoundly impacts cerebral microvascular function. Our findings identify Rho kinase as a key contributor to DOCA/salt‐induced endothelial dysfunction in brain.Grant Funding Source: Supported by NIH (HL‐62984, HL‐113863) VA (BX001399), Fondation Leducq and NHMRC (1053786)

ARTERIAL STIFFENING IS ASSOCIATED WITH CEREBRAL MICROVASCULAR DAMAGE IN UNTREATED HYPERTENSION

Arterial stiffening is associated with the incidence of stroke however little is known about its relationship with cerebral microvascular damage. Retinal arterioles provide important information on cerebral microvascular function thus we sought to investigate the relationship of retinal alterations

GPER1 agonist improves cerebral microvascular function after hypoxia/reoxygenation injury in male and female rats

Estrogen is a known neuro‐ and vaso‐protective agent in experimental cerebral ischemia. Recently, a novel G protein‐coupled estrogen receptor 1 (GPER1) has been identified. We investigated the mechanism of GPER1 mediated vasoreactivity and also its vasoprotective effect after hypoxia/reoxygenation (H/RO) injury. Rat cerebral penetrating arterioles from both genders were isolated, cannulated and pressurized. Vessel diameters were measured. To investigate vasomotor mechanism of the GPER1 agonist (G‐1), several inhibitors were tested. Ischemia/reperfusion (I/R) injury was simulated using H/RO. Vasomotor responses to adenosine tri‐phophate (ATP) after H/RO were measured with or without G‐1. G‐1 produced a vasodilatory response, which was partially dependent on endothelium‐derived nitric oxide (NO) but not arachidonic acid cascades and endothelial hyperpolarization factor. G‐1 treatment after H/RO injury fully restored arteriolar dilation to ATP compared to controls. In conclusion, GPER1 agonist elicited dilation, which partially caused by endothelial NO pathway and induced by direct relaxation of smooth muscle cells. Further, GPER1 agonist restored vessel function of arterioles after H/RO injury and may play an important role in estrogen fs ability to protect the cerebrovasculature against I/R injury. Support: NIH P01 NS32636, NIH R01 HL041250, NIH R01 NS30555, and KAKENHI 24890079.

G Protein–Coupled Estrogen Receptor Agonist Improves Cerebral Microvascular Function After Hypoxia/Reoxygenation Injury in Male and Female Rats

Reduced risk and severity of stroke in adult females are thought to depend on normal levels of endogenous estrogen, which is a known neuro- and vasoprotective agent in experimental cerebral ischemia. Recently, a novel G protein-coupled estrogen receptor (GPER, formerly GPR30) has been identified and may mediate the vasomotor and -protective effects of estrogen. However, the signaling mechanisms associated with GPER in the cerebral microcirculation remain unclear. We investigated the mechanism of GPER-mediated vasoreactivity and also its vasoprotective effect after hypoxia/reoxygenation (H/RO) injury. Rat cerebral penetrating arterioles from both sexes were isolated, cannulated, and pressurized. Vessel diameters were recorded by computer-aided videomicroscopy. To investigate vasomotor mechanism of the GPER agonist (G-1), several inhibitors with or without endothelial impairment were tested. Ischemia/reperfusion injury was simulated using H/RO. Vasomotor responses to adenosine triphophate after H/RO were measured with or without G-1 and compared with controls. G-1 produced a vasodilatory response, which was partially dependent on endothelium-derived nitric oxide (NO) but not arachidonic acid cascades and endothelial hyperpolarization factor. Attenuation of G-1-vasodilation by the NO synthase inhibitor and endothelium-impairment were greater in vessels from female than male animals. G-1 treatment after H/RO injury fully restored arteriolar dilation to adenosine triphophate compared with controls. GPER agonist elicited dilation, which was partially caused by endothelial NO pathway and induced by direct relaxation of smooth muscle cells. Further, GPER agonist restored vessel function of arterioles after H/RO injury and may play an important role in the ability of estrogen to protect the cerebrovasculature against ischemia/reperfusion injury.

Cerebral vasoreactivity to acetazolamide is not impaired in patients with severe sepsis

IntroductionThe pathophysiology of sepsis-associated encephalopathy (SAE) is not entirely clear, but one of the possible underlying mechanisms is the alteration of the cerebral microvascular function. The aim of the present work was to test whether cerebral vasomotor reactivity is impaired in patients with severe sepsis. MethodsPatients fulfilling the criteria of clinical sepsis and showing at least 2 organ dysfunctions were included (n = 16). Nonseptic healthy persons without previous diseases affecting cerebral vasoreactivity served as controls (n = 16). Transcranial Doppler blood flow velocities were measured at rest and at 5, 10, 15, and 20 minutes after intravenous administration of 15 mg/kg acetazolamide. The time course of the acetazolamide effect on cerebral blood flow velocity (cerebrovascular reactivity [CVR]) and the maximal vasodilatory effect of acetazolemide (cerebrovascular reserve capacity [CRC]) were compared among the groups. ResultsAbsolute blood flow velocities after administration of the vasodilator drug did not differ between control and septic patients. Assessment of the time course of the vasomotor reaction showed that patients with sepsis reacted in a similar fashion to the vasodilatory stimulus than control persons. When assessing the maximal vasodilatory ability of the cerebral arterioles to acetazolamide during vasomotor testing, we found that there was no difference in vasodilatory ability between septic and healthy subjects (CRC controls, 54.8% ± 11.1%; CRC sepsis-associated encephalopathy, 61.1% ± 34.4%; P = .49). ConclusionsWe conclude that cerebrovascular reactivity is not impaired in patients with severe sepsis. It is conceivable that cerebral vasoreactivity may be differently involved at different severity stages of the septic process.

Acetazolamide-induced cerebrovascular reactivity is impaired in sepsis-associated encephalopathy

The pathophysiology of sepsis-associated encephalopathy (SAE) is not entirely clear. One of the possible underlying mechanisms is the alteration of the cerebral microvascular function induced by the systemic inflammation. The aim of the present work was to test whether cerebral vasomotor reactivity is impaired in patients with SAE.

Impaired cerebrovascular reactivity in sepsis-associated encephalopathy studied by acetazolamide test

IntroductionThe pathophysiology of sepsis-associated encephalopathy (SAE) is not entirely clear. One of the possible underlying mechanisms is the alteration of the cerebral microvascular function induced by the systemic inflammation. The aim of the present work was to test whether cerebral vasomotor-reactivity is impaired in patients with SAE.MethodsPatients fulfilling the criteria of clinical sepsis and showing disturbance of consciousness of any severity were included (n = 14). Non-septic persons whithout previous diseases affecting cerebral vasoreactivity served as controls (n = 20). Transcranial Doppler blood flow velocities were measured at rest and at 5, 10, 15 and 20 minutes after intravenous administration of 15 mg/kgBW acetazolamide. The time course of the acetazolamide effect on cerebral blood flow velocity (cerebrovascular reactivity, CVR) and the maximal vasodilatory effect of acetazolemide (cerebrovascular reserve capacity, CRC) were compared among the groups.ResultsAbsolute blood flow velocities after adminsitration of the vasodilator drug were higher among control subjects than in SAE. Assessment of the time-course of the vasomotor reaction showed that patients with SAE reacted slower to the vasodilatory stimulus than control persons. When assessing the maximal vasodilatory ability of the cerebral arterioles to acetazolamide during vasomotor testing, we found that patients with SAE reacted to a lesser extent to the drug than did control subjects (CRC controls:46.2 ± 15.9%, CRC SAE: 31,5 ± 15.8%, P < 0.01).ConclusionsWe conclude that cerebrovascular reactivity is impaired in patients with SAE. The clinical significance of this pathophysiological finding has to be assessed in further studies.