UMLS:C0022116 - FACTA Search

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Query: UMLS:C0022116 (ischemia)
91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the possibility that vascular endothelial growth factor (VEGF) treatment could regulate KDR/Flk-1 receptor expression in endothelial cells. Bovine adrenal cortex endothelial cells were incubated with 200 pM rhVEGF165 for 0-7 days. Western blot analysis showed a 3-5-fold increase in total KDR protein following 4-day VEGF treatment. Scatchard analysis revealed that VEGF induced a 2-3-fold increase in high affinity receptor number (5.0 x 10(4)/cell versus 2. 4 x 10(4)/cell) without significantly affecting receptor binding affinity (Kd 76 pM versus 72 pM). Quantitative polymerase chain reaction analysis demonstrated a 3-fold increase in KDR mRNA levels following VEGF exposure. VEGF-induced KDR expression primarily occurred at the transcriptional level as demonstrated by a luciferase reporter assay system. Receptor selective mutants with wild-type KDR binding and decreased Flt-1 binding also induced KDR up-regulation; in contrast, mutants with decreased KDR binding and wild-type Flt-1 binding did not, suggesting that KDR receptor signaling mediated the increase in KDR expression. Inhibition of tyrosine kinase, Src tyrosine kinase, protein kinase C, and mitogen-activated protein kinase activities all blocked VEGF-induced KDR up-regulation. Finally, co-incubation of nitric-oxide synthase inhibitors with VEGF had no significant effect on KDR expression, but 100 microM sodium nitroprusside, a NO donor, significantly inhibited VEGF-induced KDR up-regulation, indicating that NO negatively regulates KDR expression. In conclusion, our data demonstrate that VEGF binding to the KDR receptor tyrosine kinase results in an increase in KDR receptor gene transcription and protein expression. Thus, KDR up-regulation induced by VEGF may represent an important positive feedback mechanism for VEGF action in tumor and ischemia-induced angiogenesis.
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PMID:Homologous up-regulation of KDR/Flk-1 receptor expression by vascular endothelial growth factor in vitro. 979 18

Although the vascular endothelial growth factor (VEGF)/VEGF receptor system plays a critical role in the pathogenesis of ischemic retinal neovascular diseases such as diabetic retinopathy, regulation of VEGF receptor expression in ischemic retina has not been fully investigated in vivo. Accordingly, we studied the regulation of Flt-1 (VEGFR-1) and KDR/Flk-1 (VEGFR-2) expression in a mouse model of ischemia-induced retinal neovascularization. Immunohistochemistry for Flt-1 and KDR/Flk-1 revealed that, in hypoxic retina, the immunoreactivity of KDR/Flk-1 was increased in both intensity and extent of involvement in the vessels near the avascular area, particularly at the neovascular tufts, but that the pattern of Flt-1 expression in hypoxic retina was almost the same as that of control animals. The number of KDR/Flk-1-positive vessels was significantly increased in hypoxic retina (P < 0.01). In addition, expression of both Flt-1 and KDR/Flk-1 was observed in nonvascular cells of the neural retina. Northern blot analysis demonstrated that the mRNA levels of KDR/Flk-1 were greater in the neovascular retina of hypoxic animals than in control animals. We suggest that the increased expression of KDR/Flk-1 in vascular cells might potentiate the VEGF-mediated angiogenesis that accompanies many ischemic retinal diseases.
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PMID:Increased expression of KDR/Flk-1 (VEGFR-2) in murine model of ischemia-induced retinal neovascularization. 982 56

Vascular endothelial growth factor (VEGF) has been proposed to be among the candidate factors with the most potential to play a role in ischemia-induced collateral vessel formation. Recently, we found that VEGF activated the mitogen-activated protein kinase cascade in cultured rat cardiac myocytes. To elucidate how VEGF affects adhesive interaction of cardiac myocytes with the extracellular matrix (ECM), one of the important cell functions, we investigated the molecular mechanism of activation of focal adhesion-related proteins, especially focal adhesion kinase (p125(FAK)), in cultured rat cardiac myocytes. We found that the 2 VEGF receptors, KDR/Flk-1 and Flt-1, were expressed in cardiac myocytes and that KDR/Flk-1 was significantly tyrosine phosphorylated on VEGF stimulation. VEGF induced tyrosine phosphorylation and activation of p125(FAK) as well as tyrosine phosphorylation of paxillin; this was accompanied by subcellular translocation of p125(FAK) from perinuclear sites to the focal adhesions. This VEGF-induced activation of p125(FAK) was inhibited partially by the tyrosine kinase inhibitors genistein and tyrphostin. Activation of p125(FAK) was accompanied by its increased association with adapter proteins GRB2, Shc, and nonreceptor type tyrosine kinase p60(c-src). Furthermore, we confirmed that VEGF induced a significant increase in adhesive interaction between cardiac myocytes and ECM using an electric cell-substrate impedance sensor. These results strongly suggest that p125(FAK) is one of the most important components in VEGF-induced signaling in cardiac myocytes, playing a critical role in adhesive interaction between cardiac myocytes and ECM.
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PMID:Vascular endothelial growth factor induces activation and subcellular translocation of focal adhesion kinase (p125FAK) in cultured rat cardiac myocytes. 1034 94

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

Diabetic retinopathy (DR) still remains the leading cause of blindness in the working population of Japan and western world, though therapies such as retinal photocoagulation and vitrectomy can be remarkably effective when administered at an appropriate stage in the disease process. Consequently, there is a need for further investigation of the pathogenesis of DR to develop better therapy. DR is characterized by gradually progressive alterations in the retinal microvasculature, leading to three fundamental morbidities: 1. vascular hyperpermeability, 2. vascular occlusion, and 3. neovascularization. Recent studies have revealed that hyperglycemia causes several metabolic disorders which cause DR directly or indirectly through the abnormal expression of cytokines including vascular endothelial growth factor (VEGF). In this study, we performed precise tests of the correlation between intraocular VEGF and the three fundamental changes in the diabetic retina mentioned above. Ultrastructural study of the human retina revealed that two major pathways are responsible for hyperpermeability of diabetic retinal vessels, i.e., intercellular or paracellular transport (opening of the tight junctions) and intracellular or transcellular transport (caveolae, intracytoplasmic vesicles, and fenestration). All these pathways were induced by intravitreal injection of VEGF. The major trigger of VEGF overexpression is tissue ischemia caused by vascular occlusion. However, the retinas from the eyes with background DR revealed increased expression of VEGF without apparent incidence of vascular occlusion. We have identified accumulation of advanced glycation end products (AGEs) in these retinas, and found that AGEs are a major stimulus for VEGF overexpression in background DR. Retinal vascular occlusion was caused by thrombus formation primarily in the capillary vessels. Thrombi mainly consisted of fibrin, platelets, and leucocytes in the early stage of their formation, and glial cells and macrophages were also involved in the later stage. The blood coagulation process plays an important role in fibrin formation in thrombi. The expression of tissue factor (TF), an initiator of extrinsic blood coagulation, was upregulated by VEGF in retinal vascular endothelial cells (REC). In addition, AGEs were also thrombogenic through the induction of TF expression and suppression of the expression of prostacyclin stimulating factor (PSF), which stimulate prostacyclin synthesis in vascular endothelial cells. These findings suggest that AGEs, VEGF, and TF could interact in a vicious circle because AGEs and VEGF could induce retinal vascular occlusion which results in further increase in VEGF expression. Intravitreal injection of VEGF could induce retinal neovascularization. VEGF stimulates vascular endothelial cell proliferation by binding to a specific receptor named kinase insert domain-containing receptor/fetal liver kinase (KDR/FIk-1, KDR). AGEs and basic fibroblast growth factor (bFGF) induced expression of KDR in REC, and a transcription factor Sp 1 was involved in this process. Since the expression of KDR as well as VEGF was already upregulated in the retinas with background DR, VEGF appeared to start to induce the proliferative changes long before the actual onset of proliferative DR. These findings indicated that VEGF and its receptor system plays a pivotal role all through the disease process of DR. We considered that amelioration of the activated VEGF and its receptor system could lead to the development of new therapy for DR. We have developed two novel methods to prevent retinal neovascularization by inhibiting VEGF and its receptor system. 1. An insulin sensitizing agent (troglitazone) inhibited proliferation, migration, and in vitro tube formation by REC as well as oxygen-induced retinal neovascularization in a mouse model. Thus, glycemic control by troglitazone could reduce the incidence of neovascularization in diabetic eyes. 2. (ABSTRACT TRUNCATED)
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PMID:[Cell biology of intraocular vascular diseases]. 1064 94

Preclinical studies in animal models and early results of clinical trials in patients suggest that intramuscular injection of naked plasmid DNA encoding vascular endothelial growth factor (VEGF) can promote neovascularization of ischemic tissues. Such neovascularization has been attributed exclusively to sprout formation of endothelial cells derived from preexisting vessels. We investigated the hypothesis that VEGF gene transfer may also augment the population of circulating endothelial progenitor cells (EPCs). In patients with critical limb ischemia receiving VEGF gene transfer, gene expression was documented by a transient increase in plasma levels of VEGF. A culture assay documented a significant increase in EPCs (219%, P<0.001), whereas patients who received an empty vector had no change in circulating EPCs, as was the case for volunteers who received saline injections (VEGF versus empty vector, P<0.001; VEGF versus saline, P<0.005). Fluorescence-activated cell sorter analysis disclosed an overall increase of up to 30-fold in endothelial lineage markers KDR (VEGF receptor-2), VE-cadherin, CD34, alpha(v)beta(3), and E-selectin after VEGF gene transfer. Constitutive overexpression of VEGF in patients with limb ischemia augments the population of circulating EPCs. These findings support the notion that neovascularization of human ischemic tissues after angiogenic growth factor therapy is not limited to angiogenesis but involves circulating endothelial precursors that may home to ischemic foci and differentiate in situ through a process of vasculogenesis.
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PMID:Vascular endothelial growth factor(165) gene transfer augments circulating endothelial progenitor cells in human subjects. 1086 8

Diabetic retinopathy (DR) still remains the leading cause of blindness in the working population of Japan and western world, though therapies such as retinal photocoagulation and vitrectomy can be remarkably effective when administered at an appropriate stage in the disease process. Consequently, there is a need for further investigation of the pathogenesis of DR to develop better therapy. DR is characterized by gradually progressive alterations in the retinal microvasculature, leading to three fundamental morbidities: (1) vascular hyperpermeability, (2) vascular occlusion, and (3) neovascularization. Recent studies have revealed that hyperglycemia causes several metabolic disorders which cause DR directly or indirectly through the abnormal expression of cytokines including vascular endothelial growth factor (VEGF). In this study, we performed precise tests of the correlation between intraocular VEGF and the three fundamental changes in the diabetic retina mentioned above.Ultrastructural study of the human retina revealed that two major pathways are responsible for hyperpermeability of diabetic retinal vessels, ie intercellular or paracellular transport (opening of the tight junctions) and intracellular or transcellular transport (caveolae, intracytoplasmic vesicles, and fenestration). All these pathways were induced by intravitreal injection of VEGF. The major trigger of VEGF overexpression is tissue ischemia caused by vascular occlusion. However, the retinas from the eyes with background DR revealed increased expression of VEGF without apparent incidence of vascular occlusion. We have identified accumulation of advanced glycation end products (AGEs) in these retinas, and found that AGEs are a major stimulus for VEGF overexpression in background DR. Retinal vascular occlusion was caused by thrombus formation primarily in the capillary vessels. Thrombi mainly consisted of fibrin, platelets, and leucocytes in the early stage of their formation, and glial cells and macrophages were also involved in the later stage. The blood coagulation process plays an important role in fibrin formation in thrombi. The expression of tissue factor (TF), an initiator of extrinsic blood coagulation, was upregulated by VEGF in retinal vascular endothelial cells (REC). In addition, AGEs were also thrombogenic through the induction of TF expression and suppression of the expression of prostacyclin stimulating factor (PSF), which stimulate prostacyclin synthesis in vascular endothelial cells. These findings suggest that AGEs, VEGF, and TF could interact in a vicious circle because AGEs and VEGF could induce retinal vascular occlusion which results in further increase in VEGF expression.Intravitreal injection of VEGF could induce retinal neovascularization, VEGF stimulates vascular endothelial cell proliferation by binding to a specific receptor named kinase insert domain-containing receptor/fetal liver kinase (KDR/Flk-1, KDR). AGEs and basic fibroblast growth factor (bFGF) induced expression of KDR in REC, and a transcription factor Sp 1 was involved in this process. Since the expression of KDR as well as VEGF was already upregulated in the retinas with background DR, VEGF appeared to start to induce the proliferative changes long before the actual onset of proliferative DR. These findings indicated that VEGF and its receptor system plays a pivotal role all through the disease process of DR.We considered that amelioration of the activated VEGF and its receptor system could lead to the development of new therapy for DR. We have developed two novel methods to prevent retinal neovascularization by inhibiting VEGF and its receptor system. (1) An insulin sensitizing agent (troglitazone) inhibited proliferation, migration, and in vitro tube formation by REC as well as oxygen-induced retinal neovascularization in a mouse model. Thus, glycemic control by troglitazone could reduce the incidence of neovascularization in diabetic eyes. (ABSTRACT TRUNCATED)
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PMID:Cell biology of intraocular vascular diseases 1091 68

Vascular endothelial growth factor (VEGF) is a hypoxia-inducible endothelial cell mitogen and survival factor. Its receptor VEGFR-2 (KDR/Flk-1) mediates these effects. We studied the expression of VEGF and VEGFR-2 in ischemic human and rabbit skeletal muscle by immunohistochemistry and in situ hybridization. Human samples were obtained from eight lower limb amputations because of acute or chronic critical ischemia. In chronically ischemic human skeletal muscle VEGF and VEGFR-2 expression was restricted to atrophic and regenerating skeletal myocytes, whereas in acutely ischemic limbs VEGF and VEGFR-2 were expressed diffusely in the affected muscle. Hypoxia-inducible factor-1alpha was associated with VEGF and VEGFR-2 expression both in acute and chronic ischemia but not in regeneration. Hindlimb ischemia was induced in 20 New Zealand White rabbits by excising the femoral artery. Magnetic resonance imaging and histological sections revealed extensive ischemic damage in the thigh and leg muscles of ischemic rabbit hindlimbs with VEGF expression similar to acute human lower limb ischemia. After 1 and 3 weeks of ischemia VEGF expression was restricted to regenerating myotubes and by 6 weeks regeneration and expression of VEGF was diminished. VEGFR-2 expression was co-localized with VEGF expression in regenerating myotubes. Macrophages and an increased number of capillaries were associated with areas of ischemic muscle expressing VEGF and VEGFR-2. In conclusion, two patterns of VEGF and VEGFR-2 expression in human and rabbit ischemic skeletal muscle are demonstrated. In acute skeletal muscle ischemia VEGF and VEGFR-2 are expressed diffusely in the affected muscle. In chronic skeletal muscle ischemia and in skeletal muscle recovering from ischemia VEGF and VEGFR-2 expression are restricted to atrophic and regenerating muscle cells suggesting the operation of an autocrine pathway that may promote survival and regeneration of myocytes.
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PMID:Expression of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 (KDR/Flk-1) in ischemic skeletal muscle and its regeneration. 1194 24

A subset of human peripheral blood mononuclear cells (PB-MNCs) differentiate into endothelial progenitor cells (EPCs) that participate in postnatal neovascularization. Although tissue ischemia can mobilize EPCs from bone marrow, the effects of hypoxia on differentiation and angiogenic function of EPCs are little known. We examined whether hypoxic conditioning would modulate differentiation and function of human PB-MNC-derived EPCs. A subset of PB-MNCs gave rise to EPC-like attaching (AT) cells under either normoxic or hypoxic conditions. However, hypoxia much enhanced the differentiation of AT cells from PB-MNCs compared with normoxia. AT cells released vascular endothelial growth factor (VEGF) protein and expressed CD31 and kinase insert domain receptor/VEGFR-2, endothelial lineage markers, on their surface, which were also enhanced by hypoxia. Both a neutralizing anti-VEGF mAb and a KDR-specific receptor tyrosine kinase inhibitor, SU1498, suppressed PB-MNC differentiation into EPC-like AT cells in a dose-dependent manner. Migration of AT cells in response to VEGF as examined by a modified Boyden chamber apparatus was also enhanced by hypoxia. Finally, in vivo neovascularization efficacy was significantly enhanced by in vitro hypoxic conditioning of AT cells when cells were transplanted into the ischemic hindlimb of immunodeficient nude rats. In conclusion, hypoxia directly stimulated differentiation of EPC-like AT cells from human PB-MNC culture. Moreover, hypoxic preconditioning of AT cells before in vivo transplantation is a useful means to enhance therapeutic vasculogenesis.
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PMID:Hypoxic preconditioning augments efficacy of human endothelial progenitor cells for therapeutic neovascularization. 1253 87

Endothelial progenitor cells (EPCs), which were first identified in adult peripheral blood mononuclear cells (MNCs), play an important role in postnatal neovascularization. Tissue ischemia augments mobilization of EPCs from bone marrow into the circulation and enhances incorporation of EPCs at sites of neovascularization. Two methods to obtain EPCs from bone marrow, peripheral blood or cord blood MNCs have been evaluated for therapeutic neovascularization: (1) fresh isolation using anti-CD34, anti-KDR or anti-AC133 antibody, and (2) ex vivo expansion of total MNCs. In an immunodeficient mouse model of hindlimb ischemia, systemic transplantation of human ex vivo expanded EPCs improves limb survival through the enhancement of blood flow in the ischemic tissue. A similar strategy also leads to histological and functional preservation of ischemic myocardium of nude rats. Recently, a preclinical study of catheter-based, intramyocardial transplantation ofautologous EPCs in a swine model of chronic myocardial ischemia demonstrated the therapeutic potential of cell-based therapy, with attenuation of myocardial ischemia and improvement in left ventricular function. These favorable outcomes strongly suggest a therapeutic impact of EPC transplantation in clinical settings. Further basic research, with improved understanding of the mechanisms governing homing and incorporation of EPCs, will be still necessary to optimize the methodology of the cell therapy.
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PMID:Transplantation of endothelial progenitor cells for therapeutic neovascularization. 1297 78

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