Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

VEGF is a secreted mitogen associated with angiogenesis and is also a potent vascular permeability factor. The biological role of VEGF in the ischemic brain remains unknown. This study was undertaken to investigate whether VEGF enhances cerebral microvascular perfusion and increases blood-brain barrier (BBB) leakage in the ischemic brain. Using magnetic resonance imaging (MRI), three-dimensional laser-scanning confocal microscope, and functional neurological tests, we measured the effects of administrating recombinant human VEGF(165) (rhVEGF(165)) on angiogenesis, functional neurological outcome, and BBB leakage in a rat model of focal cerebral embolic ischemia. Late (48 hours) administration of rhVEGF(165) to the ischemic rats enhanced angiogenesis in the ischemic penumbra and significantly improved neurological recovery. However, early postischemic (1 hour) administration of rhVEGF(165) to ischemic rats significantly increased BBB leakage, hemorrhagic transformation, and ischemic lesions. Administration of rhVEGF(165) to ischemic rats did not change BBB leakage and cerebral plasma perfusion in the contralateral hemisphere. Our results indicate that VEGF can markedly enhance angiogenesis in the ischemic brain and reduce neurological deficits during stroke recovery and that inhibition of VEGF at the acute stage of stroke may reduce the BBB permeability and the risk of hemorrhagic transformation after focal cerebral ischemia.
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PMID:VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain. 1101 70

The bFGF/FGFR, VEGF/VEGFR and Angiopoietin/Tie receptor system are crucial for angiogenesis and vascular remodeling. With a rat focal cerebral ischemia model, we previously reported dramatic changes in the vascular density and angiogenesis related genes in the ipsilateral cortex after 60 minutes severe ischemia. While only a small increase in the capillary density was noted in the contralateral cortex with very mild ischemia. In the present study we further reported that only Tie-1 and VEGFR-2 mRNA were significantly changed in the contralateral cortex with a p value of 0.0001 and 0.0168, respectively, and the degree of changes were very small. Interestingly, in contrast to a huge increase in the ipsilateral cortex, Tie-1 mRNA was slowly decreased after the onset of ischemia and stayed below the basal level throughout the remaining periods studied. The mechanism and significance for this decrease is not presently clear. In contrast to the ipsilateral cortex, the Angpo-1/Angpo-2 mRNA ratio was also slightly dropped below the basal level in the contralateral side in most of the ischemia-reperfusion periods studied, which is in line with the notion that small decrease in Angpo-1/Angpo-2 mRNA ratio implied small vascular remodeling activity. It is very likely that increase in this Angpo-1/Angpo-2 ratio is crucial for remodeling into large vessels and increase in Tie-1 may be crucial for capillary density increasing. Nevertheless, the detailed mechanisms and significance of differential expression of these genes and relationship to vascular remodeling remain to be characterized.
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PMID:Induction of angiogenesis related genes in the contralateral cortex with a rat three-vessel occlusion model. 1113 88

The brain's response to ischemia, which helps determine clinical outcome after stroke, is regulated partly by competing genetic programs that respectively promote cell survival and delayed cell death. Many genes involved in this response have been identified individually or systematically, providing insights into the molecular basis of ischemic injury and potential targets for therapy. The development of microarray systems for gene expression profiling permits screening of large numbers of genes for possible involvement in biological or pathological processes. Therefore, we used an oligodeoxynucleotide-based microarray consisting of 374 human genes, most implicated previously in apoptosis or related events, to detect alterations in gene expression in the hippocampus of rats subjected to 15 minutes of global cerebral ischemia followed by up to 72 hours of reperfusion. We found 1.7-fold or greater increases in the expression of 57 genes and 1.7-fold or greater decreases in the expression of 34 genes at 4, 24, or 72 hours after ischemia. The number of induced genes increased from 4 to 72 hours, whereas the number of repressed genes decreased. The induced genes included genes involved in protein synthesis, genes mutated in hereditary human diseases, proapoptotic genes, antiapoptotic genes, injury-response genes, receptors, ion channels, and enzymes. We detected transcriptional induction of several genes implicated previously in cerebral ischemia, including ALG2, APP, CASP3, CLU, ERCC3, GADD34, GADD153, IGFBP2, TIAR, VEGF, and VIM, as well as other genes not so implicated. We also found coinduction of several groups of related genes that might represent functional modules within the ischemic neuronal transcriptome, including VEGF and its receptor, NRP1; the IGF1 receptor and the IGF1-binding protein IGFBP2; Rb, the Rb-binding protein E2F1, and the E2F-related transcription factor, TFDP1; the CACNB3 and CACNB4 beta-subunits of the voltage-gated calcium channel; and caspase-3 and its substrates, ACINUS, FEM1, and GSN. To test the hypothesis that genes identified through this approach might have roles in the pathophysiology of cerebral ischemia, we measured expression of the products of two induced genes not heretofore implicated in cerebral ischemia-GRB2, an adapter protein involved in growth-factor signaling pathways, and SMN1, which participates in RNA processing and is deleted in most cases of spinal muscular atrophy. Western analysis showed enhanced expression of both proteins in hippocampus at 24 to 72 hours after ischemia, and SMN1 was localized by immunohistochemistry to hippocampal neurons. These results suggest that microarray analysis of gene expression may be useful for elucidating novel molecular mediators of cell death and survival in the ischemic brain.
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PMID:Microarray analysis of hippocampal gene expression in global cerebral ischemia. 1145 15

Neuropilin-1 and -2 (NP-1/NP-2) are transmembrane receptors that play a role in axonal guidance by binding of class III semaphorins, and in angiogenesis by binding of the vascular endothelial growth factor isoform VEGF165 and placenta growth factor (PLGF). We investigated the expression pattern of NP-1/NP-2, their co-receptors, vascular endothelial growth factor receptor-1 and -2 (VEGFR-1, VEGFR-2), and their ligands, class III semaphorins, VEGF and PLGF, following experimental cerebral ischemia in mice. By means of in situ hybridization and immunohistochemistry we observed loss of expression of class III semaphorins in neurons in the infarct/peri-infarct area. In contrast, we observed high expression of NP-1 in vessels, neurons, and astrocytes surrounding the infarct. VEGF and PLGF were upregulated in different cell types following stroke. Our results suggest a shift in the balance between semaphorins and VEGF/PLGF, which compete for NP-binding. Possibly, the loss of semaphorins facilitates binding of the competing ligands (VEGF/PLGF), thus inducing angiogenesis. In addition, the observed expression patterns further suggest a neurotrophic/neuroprotective role of VEGF/PLGF.
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PMID:Cell type-specific expression of neuropilins in an MCA-occlusion model in mice suggests a potential role in post-ischemic brain remodeling. 1193 89

Hypoxic preconditioning (8% O2, 3 h) produces tolerance 24 h after hypoxic-ischemic brain injury in neonatal rats. To better understand the ischemic tolerance mechanisms induced by hypoxia, we used oligonucleotide microarrays to examine genomic responses in neonatal rat brain following 3 h of hypoxia (8% O2) and either 0, 6, 18, or 24 h of re-oxygenation. The results showed that hypoxia-inducible factor (HIF)-1- but not HIF-2-mediated gene expression may be involved in brain hypoxia-induced tolerance. Among the genes regulated by hypoxia, 12 genes were confirmed by real time reverse transcriptase-PCR as follows: VEGF, EPO, GLUT-1, adrenomedullin, propyl 4-hydroxylase alpha, MT-1, MKP-1, CELF, 12-lipoxygenase, t-PA, CAR-1, and an expressed sequence tag. Some genes, for example GLUT-1, MT-1, CELF, MKP-1, and t-PA did not show any hypoxic regulation in either astrocytes or neurons, suggesting that other cells are responsible for the up-regulation of these genes in the hypoxic brain. These genes were expressed in normal and hypoxic brain, heart, kidney, liver, and lung, with adrenomedullin, MT-1, and VEGF being prominently induced in brain by hypoxia. These results suggest that a number of endogenous molecular mechanisms may explain how hypoxic preconditioning protects against subsequent ischemia, and may provide novel therapeutic targets for treatment of cerebral ischemia.
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PMID:Brain genomic response following hypoxia and re-oxygenation in the neonatal rat. Identification of genes that might contribute to hypoxia-induced ischemic tolerance. 1214 88

We discuss possible gene therapies for the treatment of ischemic diseases in the central nervous system (CNS). These therapies aim at the prevention of carotid artery restenosis, stimulation of angiogenesis for ischemic brain, protection of neurons against ischemia, and prevention of vasospasm due to subarachnoid hemorrhage (SAH). Carotid artery restenosis can perhaps be approached by preventing vascular smooth muscle cell proliferation via gene therapy in addition to surgical treatment. Cerebral angiogenesis therapy might be applicable to moyamoya disease. Gene therapies with VEGF and HGF to stimulate angiogenesis have been successful in muscle; however, efficacy in the CNS is unknown. Gene transfection efficiency of viral vectors has been poor in the CNS, and the safety of such vectors is questionable. Therefore, development of gene therapy is for neural protection and prevention of vasospasm due to SAH has been limited. Infusion of HVJ-AVE liposomes into monkey cerebrospinal fluid (CSF) space yielded wide-spread gene transfection. HVJ-AVE liposomes may be a promising vector for use in the human CNS. Few currently available gene therapies appear to be options for clinical treatment of cerebral ischemia despite many experimental designs. In addition to the inherent difficulties of treating the CNS, vectors and methods for introducing vectors into the CNS must be improved.
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PMID:Gene therapy for ischemic brain diseases. 1255 35

Normal tissue function depends on adequate supply of oxygen through blood vessels. Reduced oxygen supply (hypoxia) induces a variety of specific adaptation mechanisms in mammals that occur at the cellular, local and systemic level. These mechanisms are in part governed by the activation of the hypoxia-inducible transcription factors HIF-1 and HIF-2. Prolyl and asparaginyl hydroxylases as recently characterized oxygen sensors allow the regulation of HIFs that in turn modulate expression of hypoxically regulated genes such as VEGF. VEGF plays a key role in the formation of a functional and integrated vascular network required during physiological processes such as embryogenesis or female reproductive cycle as well as during a variety of pathological processes such tumor growth, wound healing, retinopathy and ischemic diseases (myocardial infarction, cerebral ischemia). However, other angiogenic factors, such as angiopoietins, PDGF, ephrins and erythropoietin are additionally needed to enable the formation of a functional vascular network. Many of these factors are activated during hypoxia although no HIF binding sites have yet been identified in the regulatory sequences of theses genes. Hypoxia-induced gene products that result in new vessel growth may be part of a self-regulated physiological protection mechanism preventing cell injury, especially under conditions of chronically reduced blood blow (chronic ischemia).
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PMID:Angiogenesis--a self-adapting principle in hypoxia. 1561 78

Acute cerebral ischemia occurs after subarachnoid hemorrhage (SAH) because of increased intracranial pressure (ICP) and decreased cerebral perfusion pressure (CPP). The effect of hyperbaric oxygen (HBO) on physiological and clinical outcomes after SAH, as well as the expressions of hypoxia-inducible factor-1alpha (HIF-1alpha) and its target genes, such as BNIP3 and VEGF was evaluated. Eighty-five male SD rats (300 to 350 g) were randomly assigned to sham, SAH, and SAH+HBO groups. Subarachnoid hemorrhage was induced by endovascular perforation. Cortical cerebral blood flow (CBF), ICP, brain water content, brain swelling, neurologic function, and mortality were assessed. HBO (100% O2, 2.8 ATA for 2 h) was initiated at 1 h after SAH. Rats were sacrificed at 24 h to harvest tissues for Western blot or for histology. Apoptotic morphology accompanied by strong immunostaining of HIF-1alpha, VEGF, and BNIP3 were observed in the hippocampus and the cortex after SAH. Increased expressions of HIF-1alpha, VEGF, and BNIP3 were quantified by Western blot. HBO reduced the expressions of HIF-1alpha, VEGF, and BNIP3, diminished neuronal damage and improved CBF and neurologic function. HBO reduced early brain injury after SAH, probably by inhibition of HIF-1alpha and its target genes, which led to the decrease of apoptosis and preservation of the blood-brain barrier function.
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PMID:Mechanisms of hyperbaric oxygen-induced neuroprotection in a rat model of subarachnoid hemorrhage. 1570 2

Secretoneurin (SN) represents a 33 amino acid neuropeptide, which is highly conserved between mammals, reptiles, birds, amphibians and fish. It is specifically expressed in endocrine, neuroendocrine and neuronal tissues. In brain, the pattern of SN expression is widespread and unique, partially overlapping with established neurotransmitters. ProSN, the precursor protein, also named secretogranin II, belongs to a class of proteins collectively called chromogranins. Changes in ProSN mRNA, which is significantly regulated by cell depolarisation, represent a useful marker for both rapid and long-lasting changes (positive and negative) of neuronal activity. Under pathophysiological conditions, especially following cellular hypoxia, SN expression can be induced in non-endocrine tissues like muscle cells, pneumocytes or tumor epithelial cells. Several biological effects were attributed to SN. SN releases dopamine from rat striatal slices in a dose dependent manner and influences neurite outgrowth in the developing cerebellum. It potently and specifically attracts monocytes, eosinophils and endothelial cells towards a concentration gradient and acts as an angiogenic cytokine comparable in potency to VEGF. Thus, SN contributes to neurogenic inflammation and might play a role in the (hypoxia-driven) induction of neo-vascularisation in ischemic diseases like peripheral or coronary artery disease, diabetic retinopathia, cerebral ischemia or in solid tumors. The signalling pathways of various biological effects have not been identified in detail, but most data point to a G-protein coupled receptor structure with respective associated intracellular events.
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PMID:Secretoneurin: a new player in angiogenesis and chemotaxis linking nerves, blood vessels and the immune system. 1610 35

VEGF and HGF are pleiotropic factors that regulate cell growth, cell motility, and morphogenesis of various types of cells. The receptors of these growth factors are expressed in neurons and endothelial cells, and are identified as neurotrophic, neuroprotective, and angiogenic factors. Indeed, gene therapy using viral vectors encoding the VEGF or HGF gene has been reported to be effective for preventing the expansion of ischemic injury. However, the safety issue of viral vectors is a major problem in clinical application. To overcome this problem, we have developed an HVJ-based non-viral vector, which achieves high-efficiency transfection rates of viral vectors with the safety of liposomes. This review discusses the feasibility of gene therapy using an HVJ-based non-viral vector containing the VEGF or HGF gene for cerebral ischemia.
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PMID:HVJ-based non-viral gene transfer method: successful gene therapy using HGF and VEGF genes in experimental ischemia. 1614 67


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