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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

VEGF is mitogenic, angiogenic, and a potent mediator of vascular permeability. VEGF causes extravasation of plasma protein in skin bioassays and increases hydraulic conductivity in isolated perfused microvessels. Reduced tissue oxygen tension triggers VEGF expression, and increased protein and mRNA levels for VEGF and its receptors (Flt-1, Flk-1/KDR) occur in the ischemic rat brain. Brain edema, provoked in part by enhanced cerebrovascular permeability, is a major complication in central nervous system pathologies, including head trauma and stroke. The role of VEGF in this pathology has remained elusive because of the lack of a suitable experimental antagonist. We used a novel fusion protein, mFlt(1-3)-IgG, which sequesters murine VEGF, to treat mice exposed to transient cortical ischemia followed by reperfusion. Using high-resolution magnetic resonance imaging, we found a significant reduction in volume of the edematous tissue 1 day after onset of ischemia in mice that received mFlt(1-3)-IgG. 8-12 weeks after treatment, measurements of the resultant infarct size revealed a significant sparing of cortical tissue. Regional cerebral blood flow was unaffected by the administration of mFlt(1-3)-IgG. These results demonstrate that antagonism of VEGF reduces ischemia/reperfusion-related brain edema and injury, implicating VEGF in the pathogenesis of stroke and related disorders.
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PMID:VEGF antagonism reduces edema formation and tissue damage after ischemia/reperfusion injury in the mouse brain. 1058 25

The angiopoietin/Tie receptor system may contribute to angiogenesis and vascular remodeling by mediating interactions of endothelial cells with smooth muscle cells and pericytes. The temporal expression of angiopoietin-1 (Angpo-1), angiopoietin-2 (Angpo-2), Tie-1, and Tie-2 mRNA was studied in a focal cerebral ischemia model in rats. The cDNA fragments obtained from reverse transcription polymerase chain reaction amplification were cloned and used as a probe to detect individual genes. Northern blot analysis showed a delayed increase of a 4.4-kb Angpo-1 transcript for up to 2 weeks after ischemia, eightfold higher than the values of the sham-operated controls. A biphasic expression of a 2.4-kb Angpo-2 transcript was noted, peaking at 24 hours (6.4-fold) and 2 weeks (4.6-fold) after ischemia. The expression of Tie-2 mRNA (4.3 kb), a receptor for Angpo-1, and Tie-1 mRNA (4.3 kb) also increased starting 24 hours after reperfusion and remained elevated for up to 2 weeks after ischemia. The temporal profiles of the expression of these genes were different from those of other angiogenic genes such as basic fibrobast growth factor/fibroblast growth factor receptor and vascular endothelial growth factor/vascular endothelial growth factor receptor and proteolytic enzymes (tissue-type plasminogen activator and urokinase plasminogen activator) and their inhibitors (plasminogen activator inhibitor-1). The expression patterns of these genes could be related to progressive tissue liquefaction and neovascularization after ischemia in this stroke model. Differential expression of these angiogenesis genes suggests the involvement of complex regulatory mechanisms that remain to be characterized.
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PMID:Induction of angiopoietin and Tie receptor mRNA expression after cerebral ischemia-reperfusion. 1069 77

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

Attention-deficit/hyperactivity disorder (AD/HD) is a common pediatric behavioral disorder associated, in part, with male preponderance and reduced regional cerebral blood flow (rCBF). However, mechanism(s) underlying male preponderance and reduced rCBF in AD/HD are unclear. The present study profiles the expression of angiogenic and hormonal factors likely to underlie these symptoms using a recently characterized AD/HD animal model, juvenile male stroke-prone spontaneously hypertensive rats (SHRSP). Because vascular endothelial growth factor (VEGF) signaling cascade and gonadal steroids are key regulators of angiogenesis and gender-based behavior, respectively, we profiled their patterns of expression in the frontal cortex of SHRSP to elucidate their roles in the genesis of AD/HD male preponderance and rCBF. Interestingly, levels of VEGF, VEGF receptors (KDR, Flt-1), endothelial nitric oxide synthase, phosphorylated Akt (pAkt), estrogen receptor-alpha, aromatase, and capillary density in sham-operated SHRSP were remarkably down-regulated, whereas androgen receptor levels were up-regulated, compared with age-matched genetic control, Wistar-Kyoto rats. Castration, estrogen, and androgen receptor antagonist (flutamide) counteracted these effects. Dihydrotestosterone, but not testosterone, reversed the beneficiary effects of castration. Estrogen receptor-beta levels remained unchanged in all groups examined. We postulate that changes in androgen metabolism that tend to up-regulate local dihydrotestosterone concentration and diminish estrogen synthesis, in the frontal cortex of juvenile male SHRSP, may lower levels and/or activity of VEGF and its signaling cascade and, subsequently, reduce rCBF. These findings could, in part, help explain the pathogenesis of reduced rCBF and male preponderance in AD/HD.
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PMID:Gonadal hormones and frontocortical expression of vascular endothelial growth factor in male stroke-prone, spontaneously hypertensive rats, a model for attention-deficit/hyperactivity disorder. 1517 44

It has been shown that vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor-2 (VEGFR-2) are upregulated in severe carotid stenosis. However, it is unknown whether carotid endarterectomy (CEA) affects serum level of these molecules. We investigated changes in concentration of VEGF and VEGFR-2 in patients undergoing carotid endarterectomy. Forty-three patients with extracranial carotid stenosis (>70%), were studied. Patients with severe vertebrobasilar stenosis, recent (<1 month) vascular event (stroke, coronary infarction, arterial thromboembolism), critical ischemia of lower extremity, recent infection, autoimmune disease or malignancy were excluded from the study. Blood samples were taken before CEA and on the second post-operative day. Thirty healthy blood donors served as a control group. We used enzyme linked immuno-absorbent assay as a method for the determination of VEGF and VEGFR-2. Pre-operative levels of VEGF (371+/-42 pg/ml) and VEGFR-2 (8424+/-356 pg/ml) were significantly elevated. There was significant decrease in both VEGF (152 pg/ml) and VEGFR-2 (1297 pg/ml) after CEA, without however reaching normal values. In asymptomatic patients and in patients with a contralateral carotid stenosis of >50%, however, the observed reduction of VEGF did not reach statistical significance. On the other hand, in the same subgroups, a major decrease of VEGFR-2 values was observed. VEGF and VEGFR-2 showed a very significant increase in serum of patients with severe carotid stenosis. These pre-operative levels decreased significantly after endarterectomy, and the changes emphasize the importance of these molecules in carotid disease progression.
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PMID:Changes in circulating levels of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 after carotid endarterectomy. 1520 28

The presence of blood vessels is a prerequisite for normal development, tissue growth, and tissue repair. However, its abnormal occurrence or absence can also potentiate disease processes. Angiogenic therapies have been used to stimulate blood vessel growth in ischemic conditions such as severe end-stage peripheral vascular disease, ischemic heart disease and stroke and for inhibition of angiogenesis in tumors. The targeting and identification of novel endothelial cell (EC) markers that can ultimately be used in angiogenic strategies is an expanding field but is limited by the availability of reagents. For instance repeated injection of mouse monoclonal antibodies (Mabs) against angiogenic EC, can result in the production of autoantibodies. Therefore, these mouse Mabs cannot be used for therapeutic purposes. Phage display technology was employed in this context to select antibodies, proteins, and peptides against known or novel EC antigens. Furthermore, technologies have been developed that enable the specific targeting of epitopes on cells including the endothelium with high-affinity/avidity antibodies. The focus for these antibody targeting strategies are markers that are unique or up-regulated on angiogenic EC including the vascular endothelial growth factor receptor (VEGFR) KDR, endoglin (CD105), and the extracellular domain B (ED-B) domain of fibronectin (FN). These markers are reviewed herein.
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PMID:Antibody phage display technologies with special reference to angiogenesis. 1574 76

Spontaneously hypertensive stroke-prone rats suffer spontaneous strokes partly as a result of abnormal cerebrovascular development. This model exhibits prehypertensive, typical hypertensive and malignant hypertensive stages. We had observed that vascular endothelial growth factor and its receptors, kinase domain region (KDR) and fms-like tyrosine kinase (Flt-1), were upregulated in the frontal cortex of spontaneously hypertensive stroke-prone rats at the typical hypertensive stage. The current study therefore investigated whether the long-term treatment with an endothelin-A/endothelin-B dual receptor antagonist, SB209670, or saline (vehicle) starting at the prehypertensive stage (6 weeks old) could reverse the upregulated vascular endothelial growth factor and its receptors; this upregulation is believed to be a compensatory adaptation for hypertension in the brain of spontaneously hypertensive stroke-prone rats. A 40% upregulation of vascular endothelial growth factor was observed in the brain of vehicle-treated spontaneously hypertensive stroke-prone rats compared with the age-matched genetic control, Wistar-Kyoto rat, and this upregulation was markedly reversed by endothelin antagonism. A similar change was found in KDR and Flt-1 expression. It is worth noting that the vascular endothelial growth factor/KDR signaling system was upregulated in the brain of spontaneously hypertensive stroke-prone rats treated with vehicle at the typical hypertensive stage, whereas the cerebral blood flow did not differ between Wistar-Kyoto and spontaneously hypertensive stroke-prone rats. We concluded that endothelin antagonism reversed the upregulated vascular endothelial growth factor and its receptors in the frontal cortex of spontaneously hypertensive stroke-prone rats at the typical hypertensive stage, and it is suggested that endothelin antagonism can reverse the hypertension-induced neurovascular remodeling in the brain of these rats.
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PMID:Brain expression of VEGF and its receptors in SHR-SP and effects of an endothelin blocker. 1583 70

Vascular endothelial growth factor (VEGF, occurring in several isoforms: VEGF-A, -B, -C, -D) is a well-known endothelial cell mitogen and vascular growth and permeability factor. Recent work done over the last few years has elucidated the important role of VEGF, which participates in the regulation of normal (physiological or therapeutic) and pathological angiogenesis (VEGF-A, VEGF-B) and lymphangiogenesis (VEGF-C, VEGF-D). VEGF has also been implicated in practically every stage of angiogenesis, yet its role in the initiation of new blood vessel creation appears to be the most important. In addition to its role as a key angiogenic factor, VEGF also possesses neurotrophic and neuroprotective activity both in the peripheral and in the central nervous system, exerting a direct action on neurons, Schwann cells, astrocytes, neural stem cells, and microglia. VEGF interacts with three subtypes of VEGF receptors occurring on the cellular membrane known as VEGFR-1 (Flt-1), VEGFR-2 (Flk-1/KDR), and VEGFR-3 (Flt-4). All these receptor types possess an internal tyrosin kinase domain. Interaction of VEGF with particular subtypes of receptors activates a circuit of signaling pathways, e.g. PI3K/Akt, Ras/Raf-MEK/Erk, eNOS/NO, and IP3/Ca2+. These participate in the generation of specific biological responses connected with proliferation, migration, increasing vascular permeability, or promoting endothelial cell survival. Recent findings from experiments performed on animals with experimentally evoked focal cerebral ischemia suggest that the neuroprotective activity of VEGF runs in parallel with its ability to promote neurogenesis and angiogenesis and that these effects may operate independently through multiple mechanisms. The above-mentioned three major features characterizing the neurobiological activity of VEGF, i.e. neuroprotection, neurogenesis, and angiogenesis, together with their possible functional link(s), provide the rationale for considering VEGF-based therapy as a promising future avenue for a more effective treatment of at least some neurodegenerative disorders and stroke. Moreover, the possibility of using neutralizing factors of VEGF or VEGF receptor antagonists may reveal a way of preventing many dangerous pathologies, including post-ischemic disturbances in cardiac and neurological disorders, tumor growth, or hypervascularization in avascular structures of the eye.
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PMID:[VEGF as an angiogenic, neurotrophic, and neuroprotective factor]. 1640 96

Spontaneous intracerebral hemorrhage (ICH) is one of the most devastating subtypes of stroke. Since angiogenesis is a fundamental process to brain development and repair by new blood vessel formation from pre-existing ones, mediated by numerous angiogenic factors including vascular endothelial growth factor (VEGF), the goal of the present work is to establish whether there is cerebral angiogenesis in rat brains with collagenase-induced ICH. Investigations were also performed to evaluate whether ICH alters expression of VEGF and its receptors Flt-1 and Flk-1. ICH was induced on adult male Sprague-Dawley rats by stereotactic injection of collagenase type VII into right globus pallidus. Angiogenesis was identified by hematoxylin-eosin stain and double immunolabeling method, and expression of VEGF and the receptors was evaluated by immunohistochemistry and quantitative real time reverse transcription-polymerase chain reaction. New vessels appeared around the hematoma and extended into it from 7 days, and 5-Bromo-2-Deoxyuridine-labeled nuclei in cerebral endothelial cells resided around the hematoma and the labeling peaked from 7 to 14 days. Expression of VEGF, Flt-1 and Flk-1 was observed in cerebral endothelial cells at the hemorrhagic basal ganglion, and increases of their mRNA persisted to 28 days. These findings suggest that ICH can induce cerebral angiogenesis and upregulation of VEGF, Flt-1 and Flk-1 and that modulation of angiogenesis via altering expression of VEGF and its receptors may be a potential strategy for promoting ICH repair.
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PMID:Cerebral angiogenesis after collagenase-induced intracerebral hemorrhage in rats. 1788 90

Vascular endothelial growth factor receptor 1 (VEGFR-1) is highly expressed in endothelial cells and regulates developmental angiogenesis by acting as a decoy receptor and trapping VEGF-A. Vascular endothelial growth factor receptor 1 is also expressed in monocytes and macrophages; mice lacking the VEGFR-1 tyrosine kinase (TK) domain (VEGFR-1 TK mice) display impaired macrophage function. Because macrophages are recruited to sites of cerebral ischemic infarcts, we hypothesized that lack of VEGFR-1 TK in bone marrow(BM) cells would affect the outcome in an experimental stroke model. We performed BM transplantation experiments in C57BL/6J mice using VEGFR-1 TK and VEGFR-1 TK mice as BM donors and analyzed cell infiltration after cerebral ischemia. There was reduced initial recruitment of VEGFR-1 TK myeloid cells into the infarcted tissue and reduced postischemic angiogenesis at 3days postischemia. By 10 days, the numbers of infiltrating cells and the densities of vessels in the infarct peri-infarct zone were similar for both groups. Neither infarct size at 3 and 10 days postischemia nor neurological performance at 24 hours was different between the experimental groups. These results support a role of VEGFR-1 signaling in the early regulation of BM infiltration and angiogenesis after brain ischemia.
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PMID:VEGFR-1 signaling regulates the homing of bone marrow-derived cells in a mouse stroke model. 2008 17


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