Three-vessel Occlusion Research Articles

Angiotensin-converting enzyme inhibitors stimulate cerebral arteriogenesis.

Arteriogenesis constitutes the most efficient endogenous rescue mechanism in cases of cerebral ischaemia. The aim of this work was to investigate whether angiotensin-converting enzyme inhibitors (ACEi) stimulates, and angiotensin II receptor type 1 blockers (ARB) inhibits cerebral collateral growth by applying a three-vessel occlusion (3-VO) model in rat. Cerebral collateral growth was measured post 3-VO (1) by assessing blood flow using the cerebrovascular reserve capacity (CVRC) technique, and (2) by assessing vessel diameters in the posterior cerebral artery (PCA) via the evaluation of latex angiographies. A stimulatory effect on arteriogenesis was investigated for ACEi administration±bradykinin receptor 1 (B1R) and 2 (B2R) blockers, and an inhibitory effect was analysed for ARB administration. Results were validated by immunohistochemical analysis and mechanistic data were collected by human umbilical vein endothelial cell (HUVEC) viability or scratch assay and monocyte (THP-1) migration assay. An inhibitory effect of ARB on arteriogenesis could not be demonstrated. However, collateral growth measurements demonstrated a significantly increased CVRC and PCA diameters in the ACEi group. ACEi stimulates cell viability and migration, which could be partially reduced by additional administration of bradykinin receptor 1 inhibitor (B1Ri). ACEi inhibits the degradation of pro-arteriogenic bradykinin derivatives, but combined ACEi+B1Ri+B1Ri (BRB) treatment did not reverse the stimulatory effect. Yet, co-administration of ACEi+BRB enhances arteriogenesis and cell migration. We demonstrate a potent stimulatory effect of ACEi on cerebral arteriogenesis in rats, presumable via B1R. However, results imply a pleiotropic and compensatory effect of ACEi on bradykinin receptor-stimulated arteriogenesis.

Animal Models of Chronic Cerebral Hypoperfusion: From Mouse to Primate.

Vascular cognitive impairment (VCI) or vascular dementia occurs as a result of brain ischemia and represents the second most common type of dementia after Alzheimer’s disease. To explore the underlying mechanisms of VCI, several animal models of chronic cerebral hypoperfusion have been developed in rats, mice, and primates. We established a mouse model of chronic cerebral hypoperfusion by narrowing the bilateral common carotid arteries with microcoils, eventually resulting in hippocampal atrophy. In addition, a mouse model of white matter infarct-related damage with cognitive and motor dysfunction has also been established by asymmetric common carotid artery surgery. Although most experiments studying chronic cerebral hypoperfusion have been performed in rodents because of the ease of handling and greater ethical acceptability, non-human primates appear to represent the best model for the study of VCI, due to their similarities in much larger white matter volume and amyloid β depositions like humans. Therefore, we also recently developed a baboon model of VCI through three-vessel occlusion (both the internal carotid arteries and the left vertebral artery). In this review, several animal models of chronic cerebral hypoperfusion, from mouse to primate, are extensively discussed to aid in better understanding of pathophysiology of VCI.

Early Detection of Cerebral Infarction After Focal Ischemia Using a New MRI Indicator.

Prolongation of the T2 relaxation time, an increase in T2-weighted signal intensity (T2-SI), and a decrease in the apparent diffusion coefficient (ADC) calculated from diffusion-weighted images (DWI) on magnetic resonance imaging (MRI) are conventional indicators of the vasogenic (interstitial) or cytotoxic (cellular) cerebral edema that develops after ischemic stroke. However, these parameters obtained on stroke imaging have not given us a precise threshold at which we can determine the viability or vulnerability of the tissue, allowing us to decide on an intervention that will help reversible tissue in the acute phase. Here, we introduce a new indicator-the essential diffusion coefficient or EDC, calculated from the T2-SI and ADC-that permits detection of irreversible brain damage after induction of experimental, focal cerebral ischemia. Our three-vessel occlusion (3-VO) method (Yang et al. Eur Neurol 71:4-18, 2014) was applied to investigate early changes on 7-T MRI. In the 3-VO model, which targetsonly a part of the cortex, animals seldom die at least within 24 h.The T2-SI and the ADC value were monitored, starting at 60min after reperfusion, and every 30-60min, for 10h after the induction of focal ischemia. The region of interest (ROI) was set in each of the following: (1) the ischemic core (the dead zone); (2) the medial border area (the dying/dead mixed zone, including the ischemic penumbra); (3) the lateral border area (the surviving zone after the ischemic stress, where the rCBF is above the threshold for death); and (4) The intact area (outside the ischemic zone). The diagnosis was made by histological analysis performed 24h after reperfusion. Significant increases in the T2-SI were observed, in ROI-1 at 1h, in ROI-2 at 2.5h, and in ROI-3 at 4h post-reperfusion (1.10, 1.11, or 1.11; > 1.10, respectively, p < 0.001). Significant reductions in the ADC were also observed in ROI-1, ROI-2, and ROI-3, at 1h post-reperfusion (0.55, 0.52, or 0.58; < 0.60, respectively, p < 0.001), indicating that both types of cerebral edema develop simultaneously in the acute phase. In the EDC analysis, from 5.0h post-reperfusion, the value in the dying/dead zone (ROI-1 and ROI-2) was consistently reduced to < 50%, showing repeated, significant differences from the value in the surviving zone (ROI-3). A reduction in the EDC to below 50% indicated irreversible tissue damage, with transformation to cerebral infarction. We could detect a sign of cerebral infarction (initial necrosis-like irreversible lesion) as early as 5.25 h after the onset of ischemia. Although the biological time that depends on the body weight must be different between mice and humans, the earliest irreversible tissue damage or tissue destruction (to have achieved the risk of hemorrhagic transformation) that progressed after invisible or silent cell death in the ultra-acute phase, seems to occur at a similar time point.

An improved three-vessel occlusion model of global cerebral ischemia in rats

We developed an improved three-vessel occlusion model of global cerebral ischemia in rats. This method consists in cessation of cerebral blood flow by accessing a. carotis communis sinistra through the ventral surface of the neck as well as tr. brachiocephalicus and a. subclavia sinistra through the first intercostal space, bypassing the pleural cavity and excluding pneumothorax. After the occlusion of the vessels that resulted in interruption of their blood flow, according to laser-Doppler flowmetry, there was a sharp decline in local cerebral blood flow in the visual cortex to 4±1% of the initial level. After restoring the level of local cerebral blood flow at the 5th minute, 10th minute, 20th minute and 24th hour of reperfusion, the levels of local cerebral blood flow were 51±7%, 41±5%, 35±8% and 54±9% of the initial level, respectively. Histo-quantitative analysis of changes in neurons of the hippocampus of rats showed that after ischemic injury, the numerical density of neurons in hippocampal zone CA1 in the observed 1mm2 region decreased by 29%, 22%, and 35%, respectively, compared to sham-operated animals (p<0.05). By the first day after global cerebral ischemia, the experimental group had shown a mean neurological deficit score equal to 7.5±1.0 and 7.9±0.7 points, followed by a decrease up to score 6.5±1.1 and 5.9±0.7 on the third day, 4.6±0.8 and 4.7±0.5 on the fifth day (on chloral hydrate and propofol anesthesia correspondently).

Mannan binding lectin-associated serine protease-2 (MASP-2) critically contributes to post-ischemic brain injury independent of MASP-1.

BackgroundComplement activation via the lectin activation pathway (LP) has been identified as the key mechanism behind post-ischemic tissue inflammation causing ischemia-reperfusion injury (IRI) which can significantly impact the clinical outcome of ischemic disease. This work defines the contributions of each of the three LP-associated enzymes—mannan-binding lectin-associated serine protease (MASP)-1, MASP-2, and MASP-3—to ischemic brain injury in experimental mouse models of stroke.MethodsFocal cerebral ischemia was induced in wild-type (WT) mice or mice deficient for defined complement components by transient middle cerebral artery occlusion (tMCAO) or three-vessel occlusion (3VO). The inhibitory MASP-2 antibody was administered systemically 7 and 3.5 days before and at reperfusion in WT mice in order to assure an effective MASP-2 inhibition throughout the study. Forty-eight hours after ischemia, neurological deficits and infarct volumes were assessed. C3 deposition and microglia/macrophage morphology were detected by immunohistochemical, immunofluorescence, and confocal analyses.ResultsMASP-2-deficient mice (MASP-2−/−) and WT mice treated with an antibody that blocks MASP-2 activity had significantly reduced neurological deficits and histopathological damage after transient ischemia and reperfusion compared to WT or control-treated mice. Surprisingly, MASP-1/3−/− mice were not protected, while mice deficient in factor B (fB−/−) showed reduced neurological deficits compared to WT mice. Consistent with behavioral and histological data, MASP-2−/− had attenuated C3 deposition and presented with a significantly higher proportion of ramified, surveying microglia in contrast to the hypertrophic pro-inflammatory microglia/macrophage phenotype seen in the ischemic brain tissue of WT mice.ConclusionsThis work demonstrates the essential role of the low-abundant MASP-2 in the mediation of cerebral ischemia-reperfusion injury and demonstrates that targeting MASP-2 by an inhibitory therapeutic antibody markedly improved the neurological and histopathological outcome after focal cerebral ischemia. These results contribute to identifying the key lectin pathway component driving brain tissue injury following cerebral ischemia and call for a revision of the presently widely accepted view that MASP-1 is an essential activator of the lectin pathway effector component MASP-2.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0684-6) contains supplementary material, which is available to authorized users.

Effect of Fluoxetine on Neurogenesis in Hippocampal Dentate Gyrus after Global Transient Cerebral Ischemia in Rats.

Changes in cerebral neurogenesis provoked by ischemia and the effect of fluoxetine on this process were studied using a three-vessel occlusion model of global transient cerebral ischemia. The global transient cerebral ischemia was modeled on male Wistar rats by transient occlusion of three major vessels originating from the aortic arch and supplying the brain (brachiocephalic trunk, left subclavian artery, and left common carotid artery). The cells expressing doublecortin (DCX, a marker of young neurons) were counted in the hippocampal dentate gyrus on day 31 after ischemia modeling. It was found that ischemia inhibited neurogenesis in the dentate gyrus in comparison with sham-operated controls (p<0.05), while fluoxetine (20 mg/kg/day) injected over 10 days after surgery restored neurogenesis to the control level (p<0.001).

Inhibition of protein tyrosine phosphatases enhances cerebral collateral growth in rats.

Arteriogenesis involves the rapid proliferation of preexisting arterioles to fully functional arteries as a compensatory mechanism to overcome circulatory deficits. Stimulation of arteriogenesis has therefore been considered a treatment concept in arterial occlusive disease. Here, we investigated the impact of inhibition of protein tyrosine phosphatases (PTPs) on cerebral arteriogenesis in rats. Arteriogenesis was induced by occlusion of one carotid and both vertebral arteries (three-vessel occlusion (3-VO)). Collateral growth and functional vessel perfusion was assessed 3-35days following 3-VO. Furthermore, animals underwent 3-VO surgery and were treated with the pan-PTP inhibitor BMOV, the SHP-1 inhibitor sodium stibogluconate (SSG), or the PTP1B inhibitor AS279. Cerebral vessel diameters and cerebrovascular reserve capacity (CVRC) were determined, together with immunohistochemistry analyses and proximity ligation assays (PLA) for determination of tissue proliferation and phosphorylation patterns after 7days. The most significant changes in vessel diameter increase were present in the ipsilateral posterior cerebral artery (PCA), with proliferative markers (PCNA) being time-dependently increased. The CVRC was lost in the early phase after 3-VO and partially recovered after 21days. PTP inhibition resulted in a significant increase in the ipsilateral PCA diameter in BMOV-treated animals and rats subjected to PTP1B inhibition. Furthermore, CVRC was significantly elevated in AS279-treated rats compared to control animals, along with hyperphosphorylation of the platelet-derived growth factor-β receptor in the vascular wall in vivo. In summary, our data indicate PTPs as hitherto unrecognized negative regulators in cerebral arteriogenesis. Further, PTP inhibition leading to enhanced collateral growth and blood perfusion suggests PTPs as novel targets in anti-ischemic treatment. PTPs exhibit negative regulatory function in cerebral collateral growth in rats. Inhibition of pan-PTP/PTP1B increases vessel PDGF-β receptor phosphorylation. PTP1B inhibition enhances arteriogenesis and cerebrovascular reserve capacity.

Pathophysiological rat model of vascular dementia: Magnetic resonance spectroscopy, microimaging and behavioral study

Chronic cerebral hypoperfusion and aging can be related to vascular dementia manifested by the decline in cognitive abilities and memory impairment. The identification of specific biomarkers of vascular disorder in early stages is important for the development of neuroprotective agents. In the present study, a three-vessel occlusion (3-VO) rat model of vascular dementia in the middle-aged rat brain was used to investigate the effect of global cerebral hypoperfusion. A multimodal study was performed using magnetic resonance spectroscopy, MR-microimaging, histology and behavioral tests. Our measurements showed a signal alteration in T2-weighted MR images, the elevation of T2 relaxation times and histologically proven neural cell death in the hippocampal area, as well as mild changes in concentration of proton and phosphorus metabolites. These changes were accompanied by mild behavioral alterations in the open field and slightly decreased habituation. The analysis of the effects of vascular pathology on cognitive functions and neurodegeneration can contribute to the development of new treatment strategies for early stages of neurodegeneration.

Endothelial progenitor cells augment collateralization and hemodynamic rescue in a model of chronic cerebral ischemia.

Surgical flow augmentation for treatment of cerebral hemodynamic impairment remains controversial. Here, we investigated the benefit of endothelial progenitor cell (EPC) treatment in a rat model of chronic cerebral hypoperfusion. At repeated time points after 3-vessel occlusion (3-VO), animals were treated with 1 × 10(6) DiI-labeled (a) ex vivo-expanded embryonic-EPC (e-EPC), (b) cyclic AMP-differentiated embryonic-endothelial progenitor-derived cells (e-EPDC as biologic control) or, (c) saline. The cerebrovascular reserve capacity (CVRC) was assessed immediately before and on days 7 and 21 after 3-VO. Structural effects were assessed by latex perfusion, immunohistochemistry, and intravital fluorescence video microscopy on day 21. Three-vessel occlusion resulted in a significant impairment of the CVRC with better functional recovery after treatment with e-EPC (16.4±8%) compared with e-EPDC (3.7±8%) or saline (6.4±9%) by day 21 (P<0.05), which was paralleled by a significant increase in the vessel diameters of the anterior Circle of Willis, a significantly higher number of leptomeningeal anastomoses and higher parenchymal capillary density in e-EPC-treated animals. Interestingly, despite in vivo interaction of e-EPC with the cerebral endothelium, e-EPC incorporation into the cerebral vasculature was not observed. Our results suggest that EPC may serve as a novel therapeutic agent in clinical trials for nonsurgical treatment of chronic cerebral hemodynamic impairment.

Phosphorylation of Thr1495 of nestin in a mouse model of cerebral ischemia and reperfusion damage

Nestin, a class VI intermediate filament protein, is expressed by neuronal progenitor cells in the subventricular zone (SVZ). In the present study, we analyzed the nestin expression and phosphorylation levels in nerve cells in a mouse model of cerebral ischemia and reperfusion. C57BL/6 mice were subjected to three-vessel occlusion for 14 min, and were killed either 1 or 4 days after the procedure. The percentages of cells in the SVZ that were positive for nestin, Thr(1495)-phosphorylated nestin or Ki67 did not significantly differ between the ischemic reperfusion and sham groups. Conversely, in the striatum and cornu ammonis 2 (CA2) regions, the mice at 4 days after ischemic reperfusion showed significantly higher numbers and percentages of nerve cells that were positive for nestin, Thr(1495)-phosphorylated nestin and Ki67 compared to results from the other groups. To our knowledge, this is the first description of phosphorylated nestin expression in neural progenitor cells in the SVZ of adult mice. In this cerebral ischemia and reperfusion mouse model, cells positive for Thr(1495)-phosphorylated nestin were increased in the striatum and CA2 field of the hippocampus; suggesting that nestin phosphorylation may play an important role in mitotically active neuronal progenitor cells.

Is there a relationship between severity of coronary artery disease and severity of erectile dysfunction?

The correlation between erectile dysfunction (ED) and coronary artery disease has been emphasized and ED has been recognized as a potential independent risk factor and/or predictor of coronary artery disease (CAD). We evaluated the association between the number of occluded coronary arteries in myocardial infarction (MI) patients with the severity of ED, and investigated the influence of related risk factors in our study group. 183 male patients who underwent coronary angiography because of acute MI from November 2009 to May 2011 were included. Following the stabilization of patients after the treatment, each patient was evaluated for erectile functionality. Risk factors such as age, diabetes, smoking, waist circumference, hypertension, and hematologic parameters were recorded. Among 183 patients with a mean age of 55.2 years who underwent coronary angiography due to acute MI, 100 (54.64 %) had ED, while the ED rate was 45.36 % (44/97) in cases of single-vessel disease, 64.5 % (31/48) in cases of two-vessel disease, and 65.7 % (25/38) in cases of three-vessel disease. The mean IIEF score was 24.2 ± 4.3, 20.4 ± 4.9 and 20.5 ± 4.2 for single or two or three-vessel disease, respectively. The presence of hypertension aggravated ED only in patients with three-vessel disease and increased total and LDL cholesterol levels in patients with single-vessel or two-vessel disease were accompanied by significantly decreasing IIEF scores. The severity of ED correlated with the number of occluded vessels documented by coronary angiography, in male patients with acute myocardial infarction. In addition, the presence of hypertension had a significant influence over erectile function only in patients with three-vessel occlusion.

Decreased Cerebral Perfusion and Oxidative Stress Result in Acute and Delayed Cognitive Impairment

Chronic cerebral hypoperfusion (CCH) is common in the pathogenesis of cognitive impairment, in which oxidative stress plays an important role. Here we describe an alternative rat model for CCH that involves two-stage, three-vessel occlusion (2s-3VO) and compare its effects with those of permanent bilateral occlusion (2VO) of the common carotid arteries. Real-time cerebral blood flow (CBF) during the surgery was monitored. Spatial learning and memory were tested with the Morris water maze, and oxidative damage was evaluated by measuring malondialdehyde (MDA) levels in both the hippocampus and cortex. We found that the CBF drop in the early stage of the 2s-3VO model was more modest than that in the 2VO model. Like 2VO rats, 2s-3VO rats showed impaired spatial learning and memory and increased MDA levels 8 weeks after surgery. Interestingly, when pooling observations from previous studies, we confirmed that oxidative damage appeared later than spatial learning and memory deficits but lasted longer than did cerebral hypoperfusion. Thus, the 2s-3VO model appears to be a suitable model for the study of CCH. Moreover, data support the notion that cognitive impairment in CCH rat models may be induced early by cerebral hypoperfusion early and in a later phase by oxidative stress.

Effects of Coenzyme Q and Creatine Supplementation on Brain Energy Metabolism in Rats Exposed to Chronic Cerebral Hypoperfusion

It is known that oxidative stress and mitochondrial dysfunction both play an important role in animal models of brain ischemia. The present study was undertaken to test whether oral supplementation of coenzyme Q10 (ubiquinone) or creatine citrate could protect against brain ischemia-induced mitochondrial damage in the rats model. Brain ischemia was induced for 50 minutes with three-vessel occlusion (3-VO). Coenzyme Q10 was administered for 30 days before the ischemic event and coenzyme Q10 or creatine citrate for 30 days post-ischemia. Moreover, the concentrations of coenzyme Q10 and α-, γ- tocopherols as well as the formation of thiobarbituric acid reactive substances (TBARS) were measured in brain mitochondria and in plasma. Transient hypoperfusion revealed significant impairment in brain energy metabolism as detected by mitochondrial oxidative phosphorylation as well as decreased concentrations of brain and plasma endogenous antioxidants and increased formation of TBARS in plasma. When compared with the ischemic group, supplementation of coenzyme Q10 was ineffective as a preventive agent. However, the positive effect of therapeutic coenzyme Q10 supplementation was supported by the oxygen consumption values (p < 0.05) and ATP production (p < 0.05) in brain mitochondria, as well as by increased concentration of coenzyme Q9 (p < 0.05) and concentration of α-tocopherol (p < 0.05) in brain mitochondria and by increased concentration of α-tocopherol (p < 0.05) and γ-tocopherol in plasma. This suggests that coenzyme Q10 therapy involves resistance to oxidative stress and improved brain bioenergetics, when supplemented during reperfusion after ischemic brain injury.

Acetylsalicylic Acid, but Not Clopidogrel, Inhibits Therapeutically Induced Cerebral Arteriogenesis in the Hypoperfused Rat Brain

This study investigated the effects of acetylsalicylic acid (ASA) and clopidogrel, standardly used in the secondary prevention of vascular occlusions, on cerebral arteriogenesis in vivo and in vitro. Cerebral hypoperfusion was induced by three-vessel occlusion (3-VO) in rats, which subsequently received vehicle, ASA (6.34 mg/kg), or clopidogrel (10 mg/kg). Granulocyte colony-stimulating factor (G-CSF), which enhanced monocyte migration in an additional cell culture model, augmented cerebrovascular arteriogenesis in subgroups (40 μg/kg). Cerebrovascular reactivity and vessel diameters were assessed at 7 and 21 days. Cerebrovascular reserve capacity was completely abolished after 3-VO and remained severely compromised after 7 (-14±14%) and 21 (-5±11%) days in the ASA groups in comparison with controls (4±5% and 10±10%) and clopidogrel (4±13% and 10±8%). It was still significantly decreased when ASA was combined with G-CSF (1±4%) compared with G-CSF alone (20±8%). Posterior cerebral artery diameters confirmed these data. Monocyte migration into the vessel wall, improved by G-CSF, was significantly reduced by ASA. Acetylsalicylic acid, but not clopidogrel, inhibits therapeutically augmented cerebral arteriogenesis.

The Impact of Volume Reduction on Early and Long-Term Outcomes in Surgical Ventricular Restoration for Severe Heart Failure

Recent published results suggest no additive benefit to surgical ventricular restoration (SVR) when combined with coronary artery bypass grafting. However, there may still be a subgroup of patients with severe heart failure who can benefit from this procedure. We reviewed our institutional experience with SVR to determine early and late outcomes based on volume reduction. We retrospectively reviewed our SVR patients (January 2002 to April 2008) with follow-up to March 2009. Baseline comorbidities, operative data, and postoperative outcomes were assessed by chart review, phone calls, and mailings. Survival was modeled using the Kaplan-Meier method. Cardiac magnetic resonance imaging, myocardial perfusion scans, and echocardiography assessed cardiac function, candidacy for SVR, and volume reduction. We reviewed 87 consecutive SVR patients (69 men). Mean age at operation was 61.1 years. Preoperatively, all patients had congestive heart failure, with 80 (92%) at New York Heart Association III/IV. All patients underwent preoperative viability studies. Three-vessel occlusion exceeding 50% was present in 69 (79%). After SVR, ejection fraction improved from 0.236 to 0.332 (p<0.001). Preoperative and postoperative magnetic resonance imaging in 26 patients (30.0%) showed a 30.8% reduction in left ventricular end systolic volume index. At follow-up, 51 of 66 (77%) improved to New York Heart Association I/II. One intraoperative death occurred. Preoperative left ventricular end systolic volume index of 80 to 120 was associated with improved survival (73% at 3 years). SVR is a surgical option for appropriately selected patients with severe congestive heart failure. In these high-risk patients, SVR successfully increased ejection fraction and decreased symptoms. A left ventricular end systolic volume index of 80 to 120 may be the ideal range for SVR procedures.

Leptin Augments Cerebral Hemodynamic Reserve after Three-Vessel Occlusion: Distinct Effects on Cerebrovascular Tone and Proliferation in a Nonlethal Model of Hypoperfused Rat Brain

The adipocytokine leptin has distinct functions regulating vascular tone, inflammation, and collateral artery growth. Arteriogenesis is an inflammatory process and provides a mechanism to overcome the effects of vascular obstruction. We, therefore, tested the effects of leptin in hypoperfused rat brain (three-vessel occlusion). Systemic leptin administration for 1 week after occlusion surgery increased cerebral hemodynamic reserve similar to granulocyte-macrophage colony-stimulating factor (GM-CSF), as indicated by improved CO(2) reactivity (vehicle 0.53%±0.26% versus leptin 1.05%±0.6% per mm Hg arterial pCO(2), P<0.05). Infusion of microspheres under maximal vasodilation failed to show a positive effect of leptin on cerebral perfusion (vehicle 64.9%±4.5% versus leptin 66.3%±7.0%, occluded/nonoccluded hemisphere). Acute treatment with GM-CSF led to a significant increased CO(2) reactivity and cerebral perfusion (79.2%±8.1% versus 64.9%±4.5%, P<0.05). Vasoconstrictive response of isolated rat carotid artery rings, after phenylephrine was attenuated at 24 hours following preincubation with leptin, was unaffected by removal of endothelium but abrogated by coculture with N-(omega)-nitro-L-arginine methylester, pointing toward an inducible nitric oxide synthase-mediated mechanism. In chronic cerebral hypoperfusion, acute leptin treatment restored the hemodynamic reserve of the cerebral vasculature through its effects on vascular tone, while leaving vascular outward remodeling unaffected. Our results, for the first time, reveal a protective role of leptin on vascular function in hemodynamically compromised brain tissue.

Limb salvage after delayed diagnosis for blunt traumatic infrapopliteal occlusion

Infrapopliteal occlusion is uncommon after blunt trauma, and limb salvage after delayed diagnosis is even rarer. We present the case of a 56-year-old man who had complex lower leg orthopedic fractures along with a reportedly normal pulse examination with an 11-day diagnostic delay of limb-threatening ischemia requiring distal revascularization. This case illustrates an incidence of delayed infrapopliteal three-vessel occlusion with successful revascularization and subsequent endovascular management to maintain patency. We describe the workup and treatment of delayed infrapopliteal occlusion and a review of the current literature on this topic.

Minimally invasive surgical approach for 3-vessel occlusion (3-VO) as a model of vascular dementia in the rat: Brain bioenergetics assay

Brain energy disorders and oxidative stress due to chronic hypoperfusion are considered to be a major risk factor in the pathogenesis of dementia. The aim of our study was to evaluate changes of brain creatine kinase (BB-CK) reaction during oxidative stress in rats exposed to permanent three-vessel occlusion (3-VO).

Minimally invasive surgical approach for three-vessel occlusion as a model of vascular dementia in the rat-brain bioenergetics assay

Brain energy disorders and oxidative stress due to chronic hypoperfusion are considered to be major risk factors in the pathogenesis of dementia. The aim of our study was to evaluate changes of the brain creatine kinase (BB-CK) reaction and mitochondrial respiratory chain function in male Wistar rats exposed to chronic cerebral hypoperfusion. Three-vessel occlusion (3-VO) was accomplished without thoracotomy using a minimally-invasive surgical approach for the occlusion of the brachiocephalic trunk and the left common carotid artery (CCA). The forward rate constant of creatine kinase ( k for) was measured in vivo by saturation transfer of 31P magnetic resonance spectroscopy (MRS) at 2 and 10 weeks of permanent 3-VO. The function of the mitochondrial respiratory chain in vitro was assessed polarographically at 10 weeks after 3-VO. When compared to the controls, the significant 42% reduction of k for at 2 resp. 10 weeks indicated disorders in brain energy metabolism, which is in agreement with the 12% decrease of the oxidative phosphorylation coefficient (ADP:O) and with the 14% decrease of the oxidative phosphorylation rate (OPR) measured in isolated mitochondria. Oxidative modification of the creatine kinase system (inactivation of enzymes) and metabolic disorders due to chronic 3-VO, thus, may participate in vascular cognitive impairment and neuronal degeneration.

In vivo cerebromicrovasculatural visualization using 3D ΔR2-based microscopy of magnetic resonance angiography (3DΔR2-mMRA)

This study proposed a novel methodology for depicting cerebral small vessels including veins, arterioles, and venules, called 3DΔR2-mMRA (three-dimensional, steady-state ΔR2-based, and flow-independent microscopic magnetic resonance angiography). The ΔR2 map calculated by a fast spin-echo imaging technique before and after the injection of an iron-oxide contrast agent was used to delineate the relative cerebral blood volume, primarily to microvasculature. The proposed 3DΔR2-mMRA method, which employs 3D reconstruction techniques, can simultaneously provide high-resolution 3D information on the cerebral anatomy, in vivo microvascular architecture, and hemodynamic response, which can be used to evaluate pathological microvascular changes over time in cerebromicrovascular disease. Since spin-echo-based ΔR2 imaging was applied, the inflow effects, susceptibility artifacts, and the overestimation of vessel size in brain were reduced. A well-defined three-vessel occlusion model in the rat was performed to evaluate the capability of the proposed method in evaluating alterations to the microvasculature.