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

In vitro studies suggest that vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) may stimulate release of nitric oxide (NO) from endothelial cells. To investigate the hemodynamic consequences of recombinant VEGF/VPF administered in vivo, recombinant human VEGF/VPF was administered as a bolus dose of 500 micrograms to anesthetized (n = 6) or conscious (n = 5) New Zealand White rabbits, as well as anesthetized rabbits with diet-induced hypercholesterolemia (HC; n = 7). Anesthetized Yorkshire farm pigs (no specific dietary pretreatment) were studied before and after receiving 500 micrograms intravenous (IV; n = 5) or intracoronary (IC; n = 5) VEGF/VPF. In anesthetized, normal rabbits, mean arterial pressure (MAP) fell by 20.5 +/- 1.4% (P < .05 versus baseline) within 3 minutes after IV VEGF/VPF. Pretreatment with N omega-nitro-L-arginine caused a significant inhibition of VEGF/VPF-induced hypotension. In conscious, normal rabbits, VEGF/VPF produced a consistent though lesser reduction in MAP. The fall in MAP induced by VEGF/VPF in anesthetized, HC rabbits (21.5 +/- 2.5% from baseline) was no different from that observed in normal anesthetized rabbits. In pigs, both IV and IC administration of VEGF/VPF produced a prompt reduction in MAP. Heart rate increased, while cardiac output, stroke volume, left atrial pressure, and total peripheral resistance all declined to a similar, statistically significant degree in both IV and IC groups. Epicardial echocardiography disclosed neither global nor segmental wall motion abnormalities in response to VEGF/VPF. We conclude that (1) VEGF/VPF-stimulated release of NO, previously suggested in vitro, occurs in vivo; (2) this finding suggests that functional VEGF/VPF receptors are present on quiescent adult endothelium, consistent with a maintenance function for VEGF/VPF, which may include regulation of NO; and (3) the preserved response of HC rabbits suggests that endothelial cell receptors for VEGF/VPF are spared in the setting of hypercholesterolemia.
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PMID:Vascular endothelial growth factor/vascular permeability factor produces nitric oxide-dependent hypotension. Evidence for a maintenance role in quiescent adult endothelium. 940 57

The arterial wall is structurally and functionally compartmentalized. Each compartment is characterized by a specific cell type and by specific interactions. The endothelial compartment interacts with circulating blood, and the adventitial compartment with the surrounding tissue. The media, which contains the effector smooth muscle cells, perceives centrifugal messages from the endothelium and centripetal messages from metabolically active tissues, from adventitial nerve endings, and from peptides produced in the interstitium. The degree of contraction or relaxation of the vascular smooth muscle cells characterizes the general vasomotor tone, which governs the local blood pressure level and distributes the flow according to metabolic needs. The main physiologic vasoactive agent is nitric oxide (NO) and is produced by the endothelium. In disease states, other agents can become predominant in centrifugal parietal messages. NO is produced by type 3 NO synthase, an enzyme that is constitutively expressed by endothelial cells. The activity of this enzyme on its substrate, arginine, is regulated by the concentration of free calcium and by intracellular phosphorylations. Several peptides, including receptors, are coupled to the phospholipase C pathway in the endothelial cell; endothelial growth factors such as FGF and VEGF, enhance the activity of endothelial NO synthase. However, the main physiologic factor responsible for endothelial NO synthase activation is the shearing stress produced by friction of the flowing blood against the immobile vessel wall. This shearing stress constantly adjusts the diameter of conductance vessels to peripheral metabolic needs. Expression of endothelial NO synthase is modulated by the chronic effects of the same agents. NO has a vasodilating effect that is mediated by the generation of cyclic GMP. Cyclic GMP and cyclic AMP are the main second messengers in smooth muscle cell relaxation. NO binds to a heme-protein, soluble guanylate cyclase, that converts GMP to cyclic GMP. Kinase-G is the main target for cyclic GMP in the smooth muscle cell. Kinase-G phosphorylates phospholambans and releases the repumping activity of calcium ATPase. More importantly, kinase-G phosphorylates the protein G that links seven-domain membrane-spanning receptors to phospholipases, thus inhibiting coupling between the ligand-receptors interaction and the intracellular signaling process that leads to contraction. NO can relax the smooth muscle cell only in the presence of a preexisting contractile tone. Conversely, absence of NO enhances the preexisting contractile tone. All these notions can be analyzed via the experimental model of L-NAME-induced chronic NO synthase blockade in rats. The decrease in parietal cyclic GMP seen in this model is associated with an increase in contractile tone that translates into systemic arterial hypertension. The increase in contractile tone can be blocked by renin-angiotensin system inhibitors. Chronic blockade of NO production rapidly induces vascular wall phenotype changes that lead to renal failure, ischemic stroke, and fibrosis of target organs. These phenotype changes may be related to the increase in the oxidative potential of the various types of parietal cells, as suggested by the abnormal presence of inflammatory cells and by the increased expression of inflammation mediators including cyclooxygenase II, inducible NO synthase, and adhesion molecules such as ICAM and VCAM. This model therefore holds promise for elucidating interactions between NO and arteriosclerosis. NO system dysfunction is also seen in other cardiovascular disorders, including congestive heart failure.
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PMID:[Role of endothelial nitric oxide in the regulation of the vasomotor system]. 976 14

The aim of the study was to investigate the influence of long-term ACE inhibition with ramipril on myocardial hypertrophy and its molecular background in spontaneously hypertensive stroke-prone rats (SHR-SP). Therefore, 1-month-old pre-hypertensive SHR-SP were randomized into three groups and exposed lifelong via drinking water to 1 mg/kg/day ramipril (anti-hypertensive dose, RHI), 10 micrograms/kg/day ramipril (non-anti-hypertensive dose, RLO) or placebo. After 15 months cardiac tissue was collected from ten rats each for immunohistochemistry and Northern blot analysis of structural proteins, proteins of the extracellular matrix and several growth factors. Results showed that RHI, but not RLO, treatment prevented development of myocyte hypertrophy (ANP). Furthermore, unlike placebo-treated rats, the ramipril-treated animals had no evidence of degeneration and loss of structural proteins (alpha -actinin), inflammatory infiltrates (CD45) and deposition of extracellular matrix proteins (collagen, fibronectin, vimentin). Only in RHI-treated animals, mRNA levels for TGF- beta(1)as well as of collagen alpha(1)(I) and fibronectin were downregulated compared to placebo-treated animals. In contrast, VEGF mRNA levels increased significantly in both groups of ramipril-treated animals v. placebo-treated SHR-SP. Thus, the reported life prolonging effect of high doses of ramipril which is associated with prevention of hypertension and hypertrophy is accompanied by prevention of the development of necrosis and fibrosis. The role of VEGF, however, seems to be independent of this effect.
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PMID:Effect of long-term ACE inhibition on myocardial tissue in hypertensive stroke-prone rats. 1042 43

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

Angiogenic growth factors and their endothelial receptors function as major regulators of blood vessel formation. The VEGF/VEGFR and the Angiopoietin/Tie2 receptor systems represent key signal transduction pathways involved in the regulation of embryonic vascular development. Inactivation of any of the genes encoding these molecules results in defective vascular development and lethality between embryonic day 8.5 and 12.5. In addition, VEGF and its receptors are also critically involved in the regulation of pathological blood vessel growth in the adult during various angiogenesis-dependent diseases that are associated with tissue hypoxia, such as solid tumor growth and ischemic diseases. It is now well established that therapeutic angiogenesis can be achieved in animal models of hind limb and myocardial ischemia by exogenously adding VEGF and/or other angiogenic growth factors. Available clinical data from human trials also suggests that patients with severe cardiovascular diseases could potentially benefit from such therapies. However, much more work needs to be done to compare the potency of different angiogenic factors or the combination thereof, as well as the best way of delivery, either as recombinant proteins, as naked DNA or via adenoviral vectors. Nevertheless, the therapeutic efficacy of simply injecting naked plasmid DNA or proteins into ischemic tissue to deliver secreted angiogenic factors is an encouraging finding. Time will show whether the adverse side effects of therapeutic angiogenesis, mainly vascular permeability and edema formation, can be minimized and angiogenic factors can be used as an effective therapy in patients for the treatment of ischemic diseases such as arterial occlusive disease, myocardial infarction, and, eventually, also stroke.
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PMID:Angiogenesis in ischemic disease. 1069 85

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 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

Breakdown or absence of vascular oxygen delivery is a hallmark of many common human diseases, including cancer, myocardial infarction, and stroke. The chief mediator of hypoxic response in mammalian tissues is the transcription factor hypoxia-inducible factor 1 (HIF-1), and its oxygen-sensitive component HIF-1alpha. A key question surrounding HIF-1alpha and the hypoxic response is the role of this transcription factor in cells removed from a functional vascular bed; in this regard there is evidence indicating that it can act as either a survival factor or induce growth arrest and apoptosis. To study more closely how HIF-1alpha functions in hypoxia in vivo, we used tissue-specific targeting to delete HIF-1alpha in an avascular tissue: the cartilaginous growth plate of developing bone. We show here the first evidence that the developmental growth plate in mammals is hypoxic, and that this hypoxia occurs in its interior rather than at its periphery. As a result of this developmental hypoxia, cells that lack HIF-1alpha in the interior of the growth plate die. This is coupled to decreased expression of the CDK inhibitor p57, and increased levels of BrdU incorporation in HIF-1alpha null growth plates, indicating defects in HIF-1alpha-regulated growth arrest occurs in these animals. Furthermore, we find that VEGF expression in the growth plate is regulated through both HIF-1alpha-dependent and -independent mechanisms. In particular, we provide evidence that VEGF expression is up-regulated in a HIF-1alpha-independent manner in chondrocytes surrounding areas of cell death, and this in turn induces ectopic angiogenesis. Altogether, our findings have important implications for the role of hypoxic response and HIF-1alpha in development, and in cell survival in tissues challenged by interruption of vascular flow; they also illustrate the complexities of HIF-1alpha response in vivo, and they provide new insights into mechanisms of growth plate development.
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PMID:Hypoxia in cartilage: HIF-1alpha is essential for chondrocyte growth arrest and survival. 1169 37

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

Understanding transcriptional changes in brain after ischemia may provide therapeutic targets for treating stroke and promoting recovery. To study these changes on a genomic scale, oligonucleotide arrays were used to assess RNA samples from periinfarction cortex of adult Sprague-Dawley rats 24 h after permanent middle cerebral artery occlusions. Of the 328 regulated transcripts in ischemia compared with sham-operated animals, 264 were upregulated, 64 were downregulated, and 163 (49.7%) had not been reported in stroke. Of the functional groups modulated by ischemia: G-protein-related genes were the least reported; and cytokines, chemokines, stress proteins, and cell adhesion and immune molecules were the most highly expressed. Quantitative reverse transcription polymerase chain reaction of 20 selected genes at 2, 4, and 24 h after ischemia showed early upregulated genes (2 h) including Narp, Rad, G33A, HYCP2, Pim-3, Cpg21, JAK2, CELF, Tenascin, and DAF. Late upregulated genes (24 h) included Cathepsin C, Cip-26, Cystatin B, PHAS-I, TBFII, Spr, PRG1, and LPS-binding protein. Glycerol 3-phosphate dehydrogenase, which is involved in mitochondrial reoxidation of glycolysis derived NADH, was regulated more than 60-fold. Plasticity-related transcripts were regulated, including Narp, agrin, and Cpg21. A newly reported lung pathway was also regulated in ischemic brain: C/EBP induction of Egr-1 (NGFI-A) with downstream induction of PAI-1, VEGF, ICAM, IL1, and MIP1. Genes regulated acutely after stroke may modulate cell survival and death; also, late regulated genes may be related to tissue repair and functional recovery.
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PMID:Genomics of the periinfarction cortex after focal cerebral ischemia. 1284 83


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