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

We examined expression of vascular endothelial growth factor (VEGF), phosphorylation of mitogen activated protein kinase (MAP) kinase (ERK1 and ERK2) and tyrosine phosphorylation in 19 patients (aged 58-90 years; mean 75) who died 1-44 days after acute ischaemic stroke. In the grey matter penumbra, 13 of 19 patients showed an increase in MAP kinase tyrosine phosphorylation (ERK1; 2.0- to 8-fold, ERK2; 2.2- to 11-fold) compared with normal contralateral tissue. In almost all cases, ERK-2 phosphorylation was higher than ERK1. Of these 13 patients, 11 also showed a general increase in tyrosine kinase phosphorylation, and eight expressed increased levels of VEGF protein (2.5- to 5-fold). In tissue examined directly from the infarct core, activation of the above proteins was not observed in the, majority of patients. In the white matter, seven of 19 patients (penumbra), and nine of 19 patients (stroke) had an increase in MAP kinase tyrosine phosphorylation (ERK1; 2.0- to 4.6-fold and ERK-2; 2.3- to 5.4-fold respectively) compared with normal contralateral tissue. There was no relationship between activation of MAP kinase and expression of VEGF. Examination of phosphorylated MAP kinase by immunohistochemistry revealed an increase in immunoreactivity in neurones, astroglial cells, reactive microglia and endothelial cells in areas surrounding infarcts, especially in areas with the highest density of microvessels. In conclusion, chronic activation of tyrosine phosphorylated events, in particular redistribution and phosphorylation of MAP kinase (ERK1/ERK2) occurs consistently in the grey matter penumbra of brain tissue following ischaemic stroke, and may be associated with increase in expression of VEGF. These signal transduction events could be important determinants of the extent of neuronal survival and/or angiogenic activity in the recovering brain tissue.
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PMID:Activation of MAP kinase (ERK-1/ERK-2), tyrosine kinase and VEGF in the human brain following acute ischaemic stroke. 1097 58

The vascular endothelial growth factor (VEGF)/VEGF receptor system plays a central regulatory role in physiological and pathological angiogenesis. During embryogenesis, the VEGF/VEGF receptor system is critically involved in the formation of the vascular system by regulating both the growth and the survival of blood vessels. In the vasculature of the adult organism, the high-affinity signaling VEGF receptor-2 (VEGFR-2) is downregulated but is reinduced during transient phases of physiological angiogenesis. Moreover, a variety of pathological conditions are associated with the upregulation of VEGF and the VEGF receptors. VEGF stimulates angiogenesis and the survival of endothelial cells in tumors, thereby enabling tumor expansion and metastasis. VEGF is also upregulated in ischemic diseases, such as coronary heart disease or stroke, and is thought to stimulate the--often insufficient--compensatory formation of blood vessels. The implication of VEGF in these pathological processes has opened up promising new therapeutic strategies. In malignancies, attempts are made to inhibit VEGF-mediated signaling and angiogenesis. In ischemic disease, the exogenous application of VEGF may enhance the formation of collaterals. However, considering the complexity of the regulatory pathways involved in the formation of new blood vessels under physiological conditions, a treatment relying on VEGF as the sole angiogenic factor may be insufficient, and the combination with other factors may improve the functionality of newly formed blood vessels and the efficacy of therapeutic angiogenesis.
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PMID:Functions of the VEGF/VEGF receptor system in the vascular system. 1112 12

Alcohol abuse has a negative impact on human health; however, epidemiological studies show that moderate consumption of ethanol (EtOH) reduces the risk of coronary heart disease, sudden cardiac death, and ischemic stroke. The mechanisms for these reductions in cardiovascular disease are not well established. Using cultured coronary artery vascular smooth muscle cells, we found that moderate levels of EtOH (10 and 20 mM) caused dose-related increases in both vascular endothelial growth factor (VEGF) mRNA (Northern blot) expression (1.9- and 2.6-fold) and VEGF protein (ELISA) expression (19 and 68%) compared with control (P < 0.05). EtOH at 0.25 g. kg(-1). day(-1) (7 days) increased VEGF mRNA expression by 1.48-fold over control, and increased vessel length density from 3.9 +/- 0.7 (control) to 6.0 +/- 0.3 mm/mm(2) (P < 0.05) in chick chorioallantoic membrane (CAM). We conclude that moderate levels of ethanol can induce VEGF expression and stimulate angiogenesis in chick CAM. Therefore, the results provide a theoretical basis for speculating that the cardiovascular-protective effects of moderate alcohol consumption may be partly mediated through VEGF-induced angiogenesis.
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PMID:Moderate levels of ethanol induce expression of vascular endothelial growth factor and stimulate angiogenesis. 1140 14

Peripheral arterial disease affects approximately 8-10 million people in the United States. Approximately one-third to one-half of these individuals are symptomatic. The risk factors that contribute to peripheral arterial disease are similar to those associated with other forms of atherosclerosis, including diabetes mellitus, cigarette smoking, hypercholesterolemia, high blood pressure, and hyperhomocysteinemia. Of these, diabetes and cigarette smoking pose the greatest risk for developing peripheral arterial disease. The prognosis of patients with these risk factors is limited because of their greater risks for myocardial infarction, stroke, and cardiovascular death. Cardiovascular mortality correlates inversely with the ankle/brachial index, and the risk of death is greatest in those with the most severe peripheral arterial disease. Treatment regimens to reduce cardiovascular morbidity and mortality in patients with peripheral arterial disease should include risk factor modification and antiplatelet therapy. The cardinal symptoms of peripheral arterial disease include intermittent claudication and rest pain, with the latter being indicative of critical limb ischemia. Therapeutic strategies that focus on improving the patient's quality of life, reducing the severity of claudication, and improving limb viability include supervised exercise training, pharmacotherapy, and revascularization. Two drugs-pentoxifylline and cilostazol-currently are approved by the Food and Drug Administration for the treatment of patients with claudication. Meta-analyses have suggested that, compared with placebo, pentoxifylline improves maximal walking distance by approximately 20-25%. Cilostazol is a phosphodiesterase type 3 inhibitor. In clinical trials, cilostazol has consistently improved maximal walking distance as compared with placebo, with the range of improvement being approximately 40-60%. Drugs that are currently under investigation include propionyl-L-carnitine, vasodilator prostaglandins, L-arginine, and the angiogenic factors, vascular endothelial growth factor and basic fibroblast growth factors.
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PMID:Medical management of peripheral arterial disease. 1140 4

This study explored the temporal expression pattern of two subtypes of vascular endothelial growth factor (VEGF) proteins and three subforms of their receptors as well as endothelial proliferation in adult rats subjected to photothrombotic ring stroke with spontaneous reperfusion in the cortical region at risk. The exposed crania of halothane-anesthetized, temperature- and blood gas-controlled male Wistar rats were irradiated with a ring laser beam started simultaneously with systemic injection of the photosensitizer erythrosin B. Rats were repeatedly injected with 5-bromodeoxyuridine (BrdU) after stroke induction. Immunohistochemistry of coronal brain sections showed that VEGF protein subtype C increased simultaneously with subtype A in the ring lesion region at 2 h after irradiation. In the cortical region at risk (i.e., the penumbra-like zone), increased VEGF-C and VEGF-A immunostaining was seen at 24 h with sustained appearance up to 72 h after ischemic onset. Correspondingly, the VEGF-C-specific receptor flt-4 and the VEGF-A receptors flt-1 and flk-1 were up-regulated in a temporal sequence similar to that of their agonist proteins in the cortical ring lesion and the region at risk. At 48 h after stroke induction, proliferating BrdU-immunopositive endothelial cells formed microvessels in the post-ischemic cortical region at risk. These vessels became more pronounced at 72 h and were still visible at 100 days after the stroke. This study suggests that VEGF-C and its receptor flt-4 may cooperate with VEGF-A and its receptors flt-1 and flk-1 to promote early angiogenesis after stroke, which may in turn contribute to spontaneous reperfusion in this focal thromboembolic stroke model.
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PMID:Vascular endothelial growth factor-A and -C protein up-regulation and early angiogenesis in a rat photothrombotic ring stroke model with spontaneous reperfusion. 1158 45

A growing body of evidence indicates that vascular growth factors and their receptors are activated after stroke, and these factors may contribute to ischemic cell damage and to angiogenesis during recovery from stroke. In this review, we focus on recent evidence for roles of vascular endothelial growth factor (VEGF) and angiopoietin 1 (Ang 1) in blood-brain barrier (BBB) leakage and angiogenesis after focal cerebral ischemia.
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PMID:Vascular endothelial growth factor and angiopoietins in focal cerebral ischemia. 1185 52

In an effort to elucidate the molecular mechanisms underlying cerebral vascular alteration after stroke, the authors measured the spatial and temporal profiles of blood-brain barrier (BBB) leakage, angiogenesis, vascular endothelial growth factor (VEGF), associated receptors, and angiopoietins and receptors after embolic stroke in the rat. Two to four hours after onset of ischemia, VEGF mRNA increased, whereas angiopoietin 1 (Ang 1) mRNA decreased. Three-dimensional immunofluorescent analysis revealed spatial coincidence between increases of VEGF immunoreactivity and BBB leakage in the ischemic core. Two to 28 days after the onset of stroke, increased expression of VEGF/VEGF receptors and Ang/Tie2 was detected at the boundary of the ischemic lesion. Concurrently, enlarged and thin-walled vessels were detected at the boundary of the ischemic lesion, and these vessels developed into smaller vessels via sprouting and intussusception. Three-dimensional quantitative analysis of cerebral vessels at the boundary zone 14 days after ischemia revealed a significant (P < 0.05) increase in numbers of vessels (n = 365) compared with numbers (n = 66) in the homologous tissue of the contralateral hemisphere. Furthermore, capillaries in the penumbra had a significantly smaller diameter (4.8 +/- 2.0 microm) than capillaries (5.4 +/- 1.5 microm) in the homologous regions of the contralateral hemisphere. Together, these data suggest that acute alteration of VEGF and Ang 1 in the ischemic core may mediate BBB leakage, whereas upregulation of VEGF/VEGF receptors and Ang/Tie2 at the boundary zone may regulate neovascularization in ischemic brain.
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PMID:Correlation of VEGF and angiopoietin expression with disruption of blood-brain barrier and angiogenesis after focal cerebral ischemia. 1191 9

Tolerance to cerebral ischemia is achieved by preconditioning sublethal stresses, such as ischemia or hypoxia, paradigms in which the decrease of O2 availability may constitute an early signal inducing tolerance. In accordance with this concept, this study shows that hypoxia induces tolerance against focal permanent ischemia in adult mice. Normobaric hypoxia (8% O2 of 1-hour, 3-hour, or 6-hour duration), performed 24 hours before ischemia, reduces infarct volume by approximately 30% when compared with controls. To elucidate the mechanisms underlying this neuroprotection, the authors investigated the effects of preconditioning on cerebral expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and its target genes, erythropoietin and vascular endothelial growth factor (VEGF). Hypoxia, whatever its duration (1 hour, 3 hours, 6 hours), rapidly increases the nuclear content of HIF-1alpha as well as the mRNA levels of erythropoietin and VEGF. Furthermore, erythropoietin and VEGF are upregulated at the protein level 24 hours after 6 hours of hypoxia. The authors' findings show that (1) hypoxia elicits a delayed, short-lasting (<72 hours) tolerance to focal permanent ischemia in the adult mouse brain; (2) HIF-1 target genes could contribute to the establishment of tolerance; and (3) this model might be a useful paradigm to further study the mechanisms of ischemic tolerance, to identify new therapeutic targets for stroke.
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PMID:Normobaric hypoxia induces tolerance to focal permanent cerebral ischemia in association with an increased expression of hypoxia-inducible factor-1 and its target genes, erythropoietin and VEGF, in the adult mouse brain. 1191 10

Intrauterine growth restriction (IUGR) is a significant cause of infant mortality and morbidity. It is now clear that IUGR infants exhibit higher rates of coronary heart disease, type 2-diabetes, hypertension and stroke as adults. Therefore, fetal growth not only impacts the outcome of the perinatal period, but also impacts adult well-being. The etiologies of IUGR are numerous, but are often associated with abnormalities in placental structure and function. The process of implantation and placentation requires the production of a plethora of growth factors, cell-adhesion molecules, extracellular matrix proteins, hormones and transcription factors. Many of these exhibit altered expression within the placenta of IUGR pregnancies. However, it has been difficult to fully assess their role during the development of placental insufficiency (PI) in the human, underscoring the need for animal models. Using an ovine model of PI-IUGR we have observed changes in the expression of vascular endothelial growth factor, placental growth factor, their common receptors, as well as angiopoietin 2 and its receptor, Tie 2. We found that changes in these growth factors can be associated with both acute and chronic changes in placental vascular structure and function. These studies and others are providing needed insight into the developmental chronology of placental insufficiency.
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PMID:Placental development in normal and compromised pregnancies-- a review. 1197 69

Although cerebral hypoperfusion caused by cerebral occlusive disease leads to cerebral ischemic events, an effective treatment has not yet been established. Recently, a novel therapeutic strategy for ischemic disease using angiogenic growth factors to expedite and/or augment collateral artery development has been proposed. Therapeutic angiogenesis might be useful for the treatment of cerebral occlusive disease. Hepatocyte growth factor (HGF) is a potent angiogenic factor, in addition to vascular endothelial growth factor (VEGF), whereas in the nervous system HGF also acts as neurotrophic factor. Therefore, we hypothesized that gene transfer of these angiogenic growth factors could induce angiogenesis, thus providing an effective therapy for cerebral hypoperfusion or stroke. In this study, we employed a highly efficient gene transfer method, the viral envelop (Hemagglutinating Virus of Japan [HVJ]-liposome) method, because we previously documented that beta-galactosidase gene could be transfected into the brain by the HVJ-liposome method. Indeed, we confirmed wide distribution of transgene expression using beta-galactosidase via injection into the subarachnoid space. Of importance, transfection of HGF or VEGF gene into the subarachnoid space 7 days before occlusion induced angiogenesis on the brain surface as assessed by alkaline phosphatase staining (P<0.01). In addition, significant improvement of cerebral blood flow (CBF) was observed by laser Doppler imaging (LDI) 7 days after occlusion (P<0.01). Unexpectedly, transfection of HGF or VEGF gene into the subarachnoid space immediately after occlusion of the bilateral carotid arteries also induced angiogenesis on the brain surface and had a significant protective effect on the impairment of CBF by carotid occlusion (P<0.01). Interestingly, coinjection of recombinant HGF with HGF gene transfer revealed a further increase in CBF (P<0.01). Here, we demonstrated successful therapeutic angiogenesis using HGF or VEGF gene transfer into the subarachnoid space to improve cerebral hypoperfusion, thus providing a new therapeutic strategy for cerebral ischemic disease.
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PMID:Gene transfer of hepatocyte growth factor to subarachnoid space in cerebral hypoperfusion model. 1201 87


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