Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adult marrow-derived cells have been shown to contribute to various nonhematologic tissues and, conversely, primitive cells isolated from nonhematopoietic tissues have been shown to reconstitute hematopoiesis. Circulating endothelial progenitor cells (EPCs) have been reported to be at least partially donor derived after allogeneic bone marrow transplantation, and shown to contribute to neovascularization in murine ischemia models. However, it is unknown whether these EPCs are actually clonally derived from the same population of stem and progenitor cells that reconstitute hematopoiesis, or from another cell population found in the marrow or mobilized blood that is transferred during transplantation. To approach this question, we characterized circulating EPCs and also endothelial cells from large vessels harvested at autopsy from rhesus macaques previously transplanted with retrovirally transduced autologous CD34-enriched peripheral blood stem cells (PBSCs). Endothelial cells were grown in culture for 21-28 days and were characterized as CD31(+) CD14(-) via flow cytometry, as acLDL(+) UEA-1(+) via immunohistochemistry, and as Flk-1(+) by reverse transcriptase-polymerase chain reaction (RT-PCR). Animals had stable vector marking in hematopoietic lineages of 2-15%. Neither cultured circulating EPCs collected in steady state (n = 3), nor endothelial cells grown from large vessels (n = 2), had detectable retroviral marking. EPCs were CD34(+) and could be mobilized into the circulation with granulocyte colony-stimulating factor. Under ex vivo culture conditions, in which CD34(+) cells were optimized to transduce hematopoietic progenitor and stem cells, there was a marked depletion of EPCs. Transduction of EPCs was much more efficient under conditions supporting endothelial cell growth. Further elucidation of the origin and in vivo behavior of EPCs may be possible, using optimized transduction conditions and a vascular injury model.
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PMID:Analysis of origin and optimization of expansion and transduction of circulating peripheral blood endothelial progenitor cells in the rhesus macaque model. 1248 99

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

This study was designed to evaluate the influence of age on the dynamic contrast-enhanced MRI of ischemic tissue. A well-established model of peripheral arterial insufficiency (i.e., the rat hindlimb ischemia after removal of femoral artery) in different age groups (i.e., young, presenescent, and senescent rats) was studied. The analysis of the MR signal demonstrated a marked accumulation of a contrast agent (Gd-DTPA) in the ischemic leg (ischemia-related enhancement, IRE). IRE was an age-related event: 4-month-old rats showed a strong IRE while 12-month-old rats and 20-month old rats showed a significantly reduced IRE in comparison to young animals. Histological analysis of the ischemic muscles revealed that there was no evidence of significant necrosis of the muscle tissue but only a weak interstitial fibrosis; CD31-immunostaining revealed a preserved microcirculatory bed.
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PMID:Dynamic MRI reveals that the magnitude of the ischemia-related enhancement in skeletal muscle is age-dependent. 1254 Dec 61

Expression of adrenomedullin, discovered as a vasodilatory peptide, is markedly up-regulated under pathological conditions such as tissue ischemia and inflammation, which are associated with neovascularization. Here, we tested the hypothesis that overly expressed adrenomedullin may augment collateral flow to ischemic tissues. We induced hindlimb ischemia in wild-type mice and injected a naked plasmid expressing human adrenomedullin or an empty vector into the ischemic muscle, followed by in vivo electroporation. Adrenomedullin markedly enhanced blood flow recovery as determined by Laser Doppler imaging. The mice treated with an empty vector suffered frequent autoamputation of the ischemic toe, which was completely prevented by adrenomedullin. Anti-CD31 immunostaining revealed that adrenomedullin significantly increased capillary density. The angiogenic effect of adrenomedullin was abrogated in endothelial nitric oxide synthase (eNOS)-deficient mice. These results indicate that adrenomedullin may promote collateral growth in response to ischemia through activation of eNOS.
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PMID:Adrenomedullin augments collateral development in response to acute ischemia. 1278 59

Carbon monoxide (CO), a byproduct of heme catalysis by heme oxygenases, has been shown to exert anti-inflammatory effects. This study examines the cytoprotective efficacy of inhaled CO during intestinal cold ischemia/reperfusion injury associated with small intestinal transplantation. Orthotopic syngenic intestinal transplantation was performed in Lewis rats after 6 hours of cold preservation in University of Wisconsin solution. Three groups were examined: normal untreated controls, control intestinal transplant recipients kept in room air, and recipients exposed to CO (250 ppm) for 1 hour before and 24 hours after surgery. In air grafts, mRNA levels for interleukin-6, cyclooxygenase-2, intracellular adhesion molecule (ICAM-1), and inducible nitric oxide synthase rapidly increased after intestinal transplant. Histopathological analysis revealed severe mucosal erosion, villous congestion, and inflammatory infiltrates. CO effectively blocked an early up-regulation of these mediators, showed less severe histopathological changes, and resulted in significantly improved animal survival of 92% from 58% in air-treated controls. CO also significantly reduced mRNA for proapoptotic Bax, while it up-regulated anti-apoptotic Bcl-2. These changes in CO-treated grafts correlated with well-preserved CD31(+) vascular endothelial cells, less frequent apoptosis/necrosis in intestinal epithelial and capillary endothelial cells, and improved graft tissue blood circulation. Protective effects of CO in this study were mediated via soluble guanylyl cyclase, because 1H-(1,2,4)oxadiazole (4,3-alpha) quinoxaline-1-one (soluble guanylyl cyclase inhibitor) completely reversed the beneficial effect conferred by CO. Perioperative CO inhalation at a low concentration resulted in protection against ischemia/reperfusion injury to intestinal grafts with prolonged cold preservation.
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PMID:Carbon monoxide inhalation protects rat intestinal grafts from ischemia/reperfusion injury. 1450 65

An 85-yr-old male presented with complaints of a 40-lb weight loss and a dull left upper quadrant abdominal pain. He also complained of decreased appetite, generalized weakness, generally not feeling well, and a dull left upper quadrant abdominal pain that was not relieved by food. He had a ventral and a left-sided inguinal hernia. Laboratory investigations revealed iron deficiency anemia, the cause of which was not apparent despite extensive investigation including computerized tomographic scans, esophagogastroduodenoscopy, and small-bowel follow-through examination. Surgical exploration for possible angiodysplasia, malignancy, and/or mesenteric ischemia revealed an incarcerated hernia, and the histopathological examination of the surgical specimen revealed high-grade angiosarcoma. The tumor showed strong positivity for vimentin and CD31 and a focal positivity for Factor VIII and CD34. At that time he was found to have hepatic metastases. He was started on thalidomide as an experimental measure with no change in the performance status and increasing evidence of necrosis in the metastatic lesion.
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PMID:Angiosarcoma of the small intestine: a possible role for thalidomide? 1471 38

Adenovirus-mediated VEGF gene delivery is being evaluated in clinical trials as a treatment for patients with vascular diseases that stem from ischemia, such as diffuse coronary artery disease and peripheral vascular disease. Although adenoviral vectors are one of the most widely utilized vectors to deliver therapeutic genes to cells, they also have a major limitation in that their inherent immunogenicity leads to the production of neutralizing antibodies that block effective repeat administration. Although this may be true of intravenous, intranasal, and other routes of administration, recent studies have indicated that it may be possible to effectively readminister adenovirus to skeletal muscle. The present study found improved efficacy after administration of AdVEGF(121.10), an E1/E3-deleted adenovirus encoding human VEGF(121) under the control of a CMV promoter in a rat hindlimb ischemia model. As expected, repeat administration of adenovirus resulted in a marked increase of circulating neutralizing antibody, yet nanogram quantities of VEGF protein were still detectable within the hindlimb skeletal muscle after a second administration of vector. The amount of VEGF protein produced after repeat administration translated into improved efficacy as evidenced by increased blood flow as measured by laser Doppler, increased vessel number upon post-mortem angiography, and an increased number of CD31-positive vessels. These findings have important implications for increasing the efficacy of adenovirus-mediated gene therapy in the treatment of peripheral vascular disease and coronary artery disease.
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PMID:Increased revascularization efficacy after administration of an adenovirus encoding VEGF(121). 1499 23

We have reported that interleukin-1 beta (IL-1 beta) upregulates cardiac expression of vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2), raising the possibility that IL-1 beta plays an important role in VEGF-mediated neovascularization. In this study, we examined the cellular mechanism for ischemia-induced neovascularization using IL-1 beta knock-out (-/-) mice. Recovery of blood perfusion in ischemic hindlimb in IL-1 beta-/- mice was markedly (43% decrease) impaired as compared with the wild-type mice. CD31(+) vessel numbers and Ki-67(+) neo-capillaries were significantly (P < 0.01) decreased 44% and 68%, respectively. IL-1 beta expression was localized in the capillary vessels in ischemic limb muscles. Ischemia-induced expressions of hypoxia-inducible factor 1 alpha (HIF-1 alpha), VEGF, its receptor VEGFR-2 and vascular cell adhesion molecule-1 (VCAM-1) were markedly inhibited in the IL-1 beta-/- mice. Hindlimb ischemia-induced an increase (1.22% out of total nuclear cell) in CD34(-)/B220(-)/CD3(-)/Flk-1(+) hematopoietic stem cell population in peripheral blood in the wild-type mice, whereas in the IL-1 beta-/- mice such increase was only 0.09%. Injection of IL-1 beta protein into the wild-type mice markedly increased the ratio of the CD34(-)/B220(-)/CD3(-)/Flk-1(+) cell population (from 0.03% to 0.7%) in the peripheral blood associated with an increase in the number of endothelial cells. Such IL-1 beta-mediated increases in cell numbers were blocked by co-injection of anti-VEGF antibody. CD34(-)/B220(-)CD3(-)Flk-1(+) cells trans-differentiated into eNOS- and CD31-expressing endothelial cells in vivo and in vitro. This study demonstrates that IL-1 beta plays a key role in ischemia-induced neovascularization by mobilizing CD34(-)/B220(-)CD3(-)Flk-1(+) endothelial precursor cells in a VEGF-dependent manner as well as by upregulating expressions of VEGF, VEGFR-2 and adhesion molecules on endothelial cells.
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PMID:Mechanism for IL-1 beta-mediated neovascularization unmasked by IL-1 beta knock-out mice. 1508 5

Multipotent adult progenitor cells, which can differentiate into mesenchymal cells as well as cells with visceral mesoderm, neuroectoderm and endoderm characteristics, have been identified in the bone marrow. We examined whether bone marrow-derived cells can differentiate into the major cell types in the brain, including neuron, astrocyte, microglia and endothelium, in response to cerebral focal ischemia under treatment with cytokines. Bone marrow cells, which were sampled from green fluorescent protein (GFP)-expressing transgenic mice, were transplanted into irradiated female C57 Black/6 mice. Two months later, the recipient mice received permanent occlusion of the middle cerebral artery, then were treated with cytokines. One month after the occlusion, GFP-expressing cells, considered to be bone marrow-derived, were identified as neurons, endothelial cells, microglias and macrophages by means of NeuN, CD31, major histocompatibility complex class I antigen, and CD45 labeling, respectively, observed with confocal microscopy. These results indicate that the bone marrow-derived cells are, at least in part, a source of neurons as well as endothelial cells generated in response to cerebral infarction, in the presence of cytokines. This finding may suggest a new therapeutic strategy to enhance neuronal and vascular regeneration after stroke in the clinical field.
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PMID:[Differentiation of adult bone marrow cells into neurons and endothelial cells in rat brain after stroke in the presence of cytokines]. 1515 77

We previously demonstrated that endothelial cells are severely damaged during renal ischemia-reperfusion and that transplantation of adult human endothelial cells into athymic nude rats subjected to renal ischemia resulted in a dramatic protection of the kidney against injury and dysfunction. Morphological studies demonstrated the engraftment of transplanted cells into renal microvasculature. The goal of the present study was to determine the potential efficacy of in vitro expanded skeletal muscle-derived stem cells (MDSC) differentiated along the endothelial lineage in ameliorating acute renal injury. MDSC obtained from the Tie-2-green fluorescent protein (GFP) mice were used as donors of differentiated and nondifferentiated stem cells. FVB mice, used as recipients, were subjected to renal ischemia and transplanted with the above MDSC. The differentiation of MDSC along the endothelial lineage was monitored by the appearance of Tie-2 promotor-driven expression of GFP. These mouse endothelial cell antigen-, endothelial nitric oxide synthase (eNOS)-, Flk-1-, Flt-1-, and CD31-positive cells engrafted into renal microvasculature and significantly protected short-term renal function after ischemia. Transplantation of nondifferentiated MDSC characterized by the expression of Sca-1 (low levels of CD34, Flk-1, and cKit, and negative for GFP, eNOS, and CD31) did not improve short-term renal dysfunction. In conclusion, the data 1) provide a rich source of MDSC, 2) delineate protocols for their in vitro expansion and differentiation along the endothelial lineage, and 3) demonstrate their efficacy in preserving renal function immediately after ischemic insult.
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PMID:Adult skeletal muscle stem cells differentiate into endothelial lineage and ameliorate renal dysfunction after acute ischemia. 1519 30


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