angiogenin and Brain-Ischemia

Topics: Angiogenesis Inducing Agents; Animals; Arteriosclerosis Obliterans; Brain Ischemia; Humans; Myocardial Ischemia; Neovascularization, Physiologic; Ribonuclease, Pancreatic

Stroke is a devastating event with a limited choice of intervention. Benzoinum is frequently used to treat stroke in traditional Chinese medicine. Our team has found that the neuroprotection of benzoinum may related to angiogenesis, but the exact biological mechanism is unclear. The objective of this study was to explore its biological mechanism of angiogenesis in cerebral ischemia model rats.. First, network pharmacology and molecular docking were performed to predict the possible targets and mechanisms of benzoinum in treating ischemic stroke. The best dose was then selected according to pharmacodynamic indexes such as those for neurological deficit, cerebral infarction rate, and brain histopathology in middle cerebral artery occlusion (MCAO) model rats. Finally, RT-PCR, Western Blot and immunohistochemical analysis were applied to verify the prediction results from molecular docking.. Network pharmacology and molecular docking demonstrated that the targets of treating cerebral ischemia were PDE4D, ACE and TTR, and the mechanism may be related to the ACE-AngI-VEGF signaling pathway. Experimental verification results suggested that 0.50 g/kg and 1.00 g/kg benzoinum could significantly protect against neurological deficit and reduce cerebral infarction rate in the cerebral cortex and hippocampus in MCAO model rats. At an optimal dose, benzoinum could significantly up-regulate VEGF, SHH and ANG-1, yet down-regulate ACE expression in MCAO model rats.. Balsamic acid is the active ingredient of benzoinum that protects against ischemic stroke and the possible mechanism is related to the promotion of angiogenesis via regulating ACE-AngI-VEGF pathway.

Topics: Animals; Brain Ischemia; Cerebral Cortex; Disease Models, Animal; Drugs, Chinese Herbal; Gene Expression Regulation; Infarction, Middle Cerebral Artery; Male; Molecular Docking Simulation; Neovascularization, Pathologic; Neuroprotective Agents; Peptidyl-Dipeptidase A; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Ribonuclease, Pancreatic; Small Molecule Libraries; Stroke; Vascular Endothelial Growth Factor A

Endothelial progenitor cells (EPCs) have been extensively investigated as a therapeutic approach for repairing the vascular system in cerebrovascular diseases. Beyond vascular regeneration per se, EPCs may also release factors that affect the entire neurovascular unit. Here, we aim to study the effects of the EPC secretome on oligovascular remodeling in a mouse model of white matter injury after prolonged cerebral hypoperfusion.. The secretome of mouse EPCs was analyzed with a proteome array. In vitro, the effects of the EPC secretome and its factor angiogenin were assessed on primary oligodendrocyte precursor cells and mature human cerebral microvascular endothelial cells (hCMED/D3). In vivo, mice were subjected to permanent bilateral common carotid artery stenosis, then treated with EPC secretome at 24 hours and at 1 week, and cognitive outcome was evaluated with the Y maze test together with oligodendrocyte precursor cell proliferation/differentiation and vascular density in white matter at 4 weeks.. Multiple growth factors, cytokines, and proteases were identified in the EPC secretome, including angiogenin. In vitro, the EPC secretome significantly enhanced endothelial and oligodendrocyte precursor cell proliferation and potentiated oligodendrocyte precursor cell maturation. Angiogenin was proved to be a key factor since pharmacological blockade of angiogenin signaling negated the positive effects of the EPC secretome. In vivo, treatment with the EPC secretome increased vascular density, myelin, and mature oligodendrocytes in white matter and rescued cognitive function in the mouse hypoperfusion model.. Factors secreted by EPCs may ameliorate white matter damage in the brain by boosting oligovascular remodeling.

Topics: Angiogenesis Inducing Agents; Animals; Brain Ischemia; Carotid Stenosis; Cell Proliferation; Culture Media, Conditioned; Cytokines; Disease Models, Animal; Endothelial Progenitor Cells; Glutathione S-Transferase pi; Humans; In Vitro Techniques; Intercellular Signaling Peptides and Proteins; Mice; Myelin Basic Protein; Oligodendrocyte Precursor Cells; Peptide Hydrolases; Platelet Endothelial Cell Adhesion Molecule-1; Receptor, Platelet-Derived Growth Factor alpha; Ribonuclease, Pancreatic; Vascular Remodeling; White Matter

Migraine has been reported as a risk factor for ischemic stroke or cardiovascular events, and dysfunction of endothelial cells has been evidenced in migraine patients. Proangiogenic factors are potential endothelial stimulators, and their disturbances can link abnormalities of endothelium with increased risk of vascular disorders. The aim of this study was to evaluate the levels of circulating proangiogenic factors in sera of migraineurs during interictal period. Fifty-two patients aged 37.9 ± 9.6 years, fulfilling International Headache Society criteria for migraine, were included in this observational case-control study. The control group included 39 healthy volunteers, matched according to age and gender. All subjects underwent full neurological examination and clinimetric evaluation with the use of: MIDAS, MIGSEV, QVM, VAS and VRS scales. Serum concentrations of vascular endothelial growth factor (VEGF), angiogenin, angiopoietin-2, thrombopoietin and Tie-2 were estimated in migraineurs and in the control group with the use of ELISA. In migraineurs during interictal period, we have found decreased serum VEGF and angiogenin concentrations compared with controls. Age of migraine onset correlated with VEGF, angiopoietin-2 and thrombopoietin concentrations. Furthermore, angiopoietin-2 level correlated with QVM score and Tie-2 with pain intensity evaluated using MIGSEV scale. In migraine patients during interictal period, depletion of VEGF and angiogenin, two cooperating proangiogenic factors, can be responsible for endothelial dysfunction and increased risk for vascular disorders.

Topics: Adult; Angiopoietin-2; Brain Ischemia; Case-Control Studies; Endothelium, Vascular; Genetic Predisposition to Disease; Humans; Lipids; Middle Aged; Migraine Disorders; Receptor, TIE-2; Ribonuclease, Pancreatic; Severity of Illness Index; Thrombopoietin; Vascular Endothelial Growth Factor A

Ischemic injuries will lead to necrotic tissue damage, and post-ischemia angiogenesis plays critical roles in blood flow restoration and tissue recovery. Recently, several types of small RNAs have been reported to be involved in this process. In this study, we first generated a rat brain ischemic model to investigate the involvement of new types of small RNAs in ischemia. We utilized deep sequencing and bioinformatics analyses to demonstrate that the level of small RNA fragments derived from tRNAs strikingly increased in the ischemic rat brain. Among these sequences, tRNA(Val)- and tRNA(Gly)-derived small RNAs account for the most abundant segments. The up-regulation of tRNA(Val)- and tRNA(Gly)-derived fragments was verified through northern blot and quantitative PCR analyses. The levels of these two fragments also increased in a mouse hindlimb ischemia model and cellular hypoxia model. Importantly, up-regulation of the tRNA(Val)- and tRNA(Gly)-derived fragments in endothelial cells inhibited cell proliferation, migration and tube formation. Furthermore, we showed that these small RNAs are generated by angiogenin cleavage. Our results indicate that tRNA-derived fragments are involved in tissue ischemia, and we demonstrate for the first time that tRNA(Val)- and tRNA(Gly)-derived fragments inhibit angiogenesis by modulating the function of endothelial cells.

Topics: Animals; Brain; Brain Ischemia; Cell Hypoxia; Cell Movement; Cell Proliferation; Computational Biology; Gene Expression Regulation; Hindlimb; Human Umbilical Vein Endothelial Cells; Humans; Male; Mice; Neovascularization, Physiologic; Proteolysis; Rats; Rats, Sprague-Dawley; Ribonuclease, Pancreatic; RNA Cleavage; RNA, Small Untranslated; RNA, Transfer, Gly; RNA, Transfer, Val; Signal Transduction

Angiogenin (ANG) is a potent angiogenic factor. The purposes of this study were to observe the change of the expression level of ANG and to identify the cell types that express ANG in the focal ischemic rat brain. The rat brain ischemia-reperfusion model was produced by a 2 h occlusion of the left middle cerebral artery with a nylon thread followed by reperfusion for 1 day, 3 days, 7 days or 14 days. The expression levels of ANG in the rat brain at each time points were determined by western blotting. The co-staining of ANG with NeuN was observed using double immunofluorescent labeling combined with confocal laser scanning microscope. We found that the expression level of ANG increased significantly in the rat brain 1 day, 3 days, and 7 days after ischemia (P<0.05), and peaked 3 days after ischemia. Double immunofluorescent labeling showed that ANG positive cells were mostly co-stained with NeuN. Our observations suggest that the level of ANG increased significantly in the rat brain after ischemia. The upregulated ANG was mostly expressed by neurons.

Topics: Analysis of Variance; Animals; Antigens, Nuclear; Blotting, Western; Brain; Brain Ischemia; Fluorescent Antibody Technique; Infarction, Middle Cerebral Artery; Male; Microscopy, Confocal; Nerve Tissue Proteins; Neurons; Random Allocation; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Ribonuclease, Pancreatic; Time Factors

To explore the mechanism of electroacupuncture (EA) in improving ischemic stroke.. The Wistar rat model of focal cerebral ischemia-reperfusion was prepared by the thread embolism method. The rats were randomly divided into a normal group, a model group, and an EA group. EA was given at bilateral "Hegu" (LI 4) in rats of the EA group. Expression of the vascular endothelial growth factor (VEGF) mRNA was detected with hybridization in situ, and expressions of the angiogenin-1 (Ang-1) and endostatin proteins were detected with the immunohistochemical method.. As compared with the normal group, the expressions of VEGF mRNA, Ang-1 protein and endostatin protein significantly increased in the model group (all P < 0.05); and when compared with the model group, the EA group showed even more significant increase in expressions of the VEGF mRNA and Ang-1 protein (both P < 0.05), but with an obvious decline in the increase of expression of endostatin protein (P < 0.05).. EA can promote angiogenesis in brain of experimental cerebral ischemic rats after reperfusion probably through up-regulating the expression of angiogenesis factors and down-regulating the expression of anti-angiogenesis factors.

Topics: Angiogenesis Modulating Agents; Animals; Brain; Brain Ischemia; Electroacupuncture; Endostatins; Gene Expression; Humans; Male; Random Allocation; Rats; Rats, Wistar; Reperfusion; Ribonuclease, Pancreatic; Vascular Endothelial Growth Factor A

To explore the mechanism of electroacupuncture (EA) in improving ischemic stroke.. A Wistar rat model of focal cerebral ischemia reperfusion was made by filament occlusion. The rats were randomly divided into a normal group, a model group, an EA group. EA was given at bilateral "Hegu" (LI 4) in the EA group. Vascular endothelial growth factor (VEGF) mRNA was detected with in situ hybridization and expression of angiogenin-1 (Ang-1) and endostatin proteins with immunohistochemical method.. The expressions of angiogenic growth factors including VEGF and Ang-1 in the EA group were significantly increased, while the expressions of endostatin was significantly decreased as compared with those in the model group (both P<0.05).. EA improving ischemic stroke is carried out possibly through up-regulating the expression of angiogenic growth factors and down-regulating the expression of antiangiogenic growth factors.

Topics: Animals; Brain; Brain Ischemia; Electroacupuncture; Endostatins; Immunohistochemistry; Male; Rats; Rats, Wistar; Reperfusion; Ribonuclease, Pancreatic; RNA, Messenger; Vascular Endothelial Growth Factor A