Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

In a previous study, we showed that in situ injection of glycosaminoglycan mimetics called RGTAs (ReGeneraTing Agents) enhanced neovascularization after skeletal muscular ischemia (Desgranges, P., Barbaud, C., Caruelle, J. P., Barritault, D., and Gautron, J. (1999) FASEB J. 13, 761-766). In the present study, we showed that the RGTA OTR4120 modulated angiogenesis in the chicken embryo chorioallantoic membrane assay, in a dose-dependent manner. We therefore investigated the effect of OTR4120 on one of the most specific angiogenesis-regulating heparin-binding growth factors, vascular endothelial growth factor 165 (VEGF165). OTR4120 showed high affinity binding to VEGF165 (Kd = 2.2 nm), as compared with heparin (Kd = 15 nm), and potentiated the affinity of VEGF165 for VEGF receptor-1 and -2 and for neuropilin-1. In vitro, OTR4120 potentiated VEGF165-induced proliferation and migration of human umbilical vein endothelial cells. In the in vivo Matrigel plug angiogenesis assay, OTR4120 in a concentration as low as 3 ng/ml caused a 6-fold increase in VEGF165-induced angiogenesis. Immunohistochemical staining showed a larger number of well differentiated VEGFR-2-expressing-cells in Matrigel sections of OTR4120-treated plug than in control sections. These findings indicate that OTR4120 enhances the VEGF165-induced angiogenesis and therefore may hold promise for treating disorders characterized by deficient angiogenesis.
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PMID:A synthetic glycosaminoglycan mimetic binds vascular endothelial growth factor and modulates angiogenesis. 1601 24

Endothelial cells respond to vascular endothelial growth factor (VEGF) to produce new blood vessels. This process of angiogenesis makes a critical contribution during embryogenesis and also in the response to ischemia in adult tissues. We have studied the intracellular trafficking of the major VEGF receptor KDR (VEGFR2). Unlike other related growth factor receptors, we find that a significant proportion of KDR is held in an endosomal storage pool within endothelial cells. We find that KDR can be delivered to the plasma membrane from this intracellular pool and that VEGF stimulates this recycling to the cell surface. KDR recycling appears to be distinct from the previously characterized Rab4- and Rab11-dependent pathways, but, instead, KDR(+) recycling vesicles contain Src tyrosine kinase and VEGF-stimulated recycling requires Src activation. Taken together, these data show that intracellular trafficking of KDR is markedly different from other receptor tyrosine kinases and suggest that the regulation of KDR trafficking by VEGF provides a novel mechanism for controlling the sensitivity of endothelial cells to proangiogenic signals.
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PMID:VEGF regulates the mobilization of VEGFR2/KDR from an intracellular endothelial storage compartment. 1663 31

Bmx/Etk non-receptor tyrosine protein kinase has been implicated in endothelial cell migration and tube formation in vitro. However, the role of Bmx in vivo is not known. Bmx is highly induced in the vasculature of ischemic hind limbs. We used both mice with a genetic deletion of Bmx (Bmx-KO mice) and transgenic mice expressing a constitutively active form of Bmx under the endothelial Tie-2 enhancer/promoter (Bmx-SK-Tg mice) to study the role of Bmx in ischemia-mediated arteriogenesis/angiogenesis. In response to ischemia, Bmx-KO mice had markedly reduced, whereas Bmx-SK-Tg mice had enhanced, clinical recovery, limb perfusion, and ischemic reserve capacity when compared with nontransgenic control mice. The functional outcomes in these mice were correlated with ischemia-initiated arteriogenesis, capillary formation, and vessel maturation as well as Bmx-dependent expression/activation of TNF receptor 2- and VEGFR2-mediated (TNFR2/VEGFR2-mediated) angiogenic signaling in both hind limb and bone marrow. More importantly, results of bone marrow transplantation studies showed that Bmx in bone marrow-derived cells plays a critical role in the early phase of ischemic tissue remodeling. Our study provides the first demonstration to our knowledge that Bmx in endothelium and bone marrow plays a critical role in arteriogenesis/angiogenesis in vivo and suggests that Bmx may be a novel target for the treatment of vascular diseases such as coronary artery disease and peripheral arterial disease.
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PMID:Critical function of Bmx/Etk in ischemia-mediated arteriogenesis and angiogenesis. 1693 10

Therapeutic induction of angiogenesis is a potential treatment for chronic ischemia. Heparan sulfate proteoglycans are known to play an important role by their interactions with proangiogenic growth factors such as vascular endothelial growth factor (VEGF). Low molecular weight fucoidan (LMWF), a sulfated polysaccharide from brown seaweeds that mimic some biological activities of heparin, has been shown recently to promote revascularization in rat critical hindlimb ischemia. In this report, we first used cultured human endothelial cells (ECs) to investigate the possible ability of LMWF to enhance the actions of VEGF(165). Data showed that LMWF greatly enhances EC tube formation in growth factor reduced matrigel. LMWF is a strong enhancer of VEGF(165)-induced EC chemotaxis, but not proliferation. In addition, LMWF has no effect on VEGF(121)-induced EC migration, a VEGF isoform that does not bind to heparan sulfate proteoglycans. Then, with binding studies using (125)I-VEGF(165), we observed that LMWF enhances the binding of VEGF(165) to recombinant VEGFR-2 and Neuropilin-1 (NRP1), but not to VEGFR-1. Surface plasmon resonance analysis showed that LMWF binds with high affinity to VEGF(165) (1.2 nm) and its receptors (5-20 nm), but not to VEGF(121). Pre-injection of LMWF on immobilized receptors shows that VEGF(165) has the highest affinity for VEGFR-2 and NRP1, as compared with VEGFR-1. Overall, the effects of LMWF were much more pronounced than those of LMW heparin. These findings suggested an efficient mechanism of action of LMWF by promoting VEGF(165) binding to VEGFR-2 and NRP1 on ECs that could help in stimulating therapeutic revascularization.
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PMID:Low molecular weight fucoidan increases VEGF165-induced endothelial cell migration by enhancing VEGF165 binding to VEGFR-2 and NRP1. 1702 97

Hypoxia inducible factor-1 alpha (HIF-1 alpha) is a key determinant of oxygen-dependent gene regulation in angiogenesis. HIF-1 alpha overexpression may be beneficial in cell therapy of hypoxia-induced pathophysiological processes, such as ischemic heart disease. To address this issue, human peripheral blood mononuclear cells (PBMNCs) were induced to differentiate into endothelial progenitor cells (EPCs), and then were transfected with either an HIF-1 alpha-expressing or a control vector and cultured under normoxia or hypoxia. Hypoxia-induced HIF-1 alpha mRNA and protein expression was increased after HIF-1 alpha transfection. This was accompanied by VEGF mRNA induction and increased VEGF secretion. Hypoxia-stimulated VEGF mRNA induction was significantly abrogated by HIF-1 alpha-specific siRNA. Functional studies showed that HIF-1 alpha overexpression further promoted hypoxia-induced EPC differentiation, proliferation and migration. The expressions of endothelial cell markers CD31, VEGFR2 (Flk-1) and eNOS as well as VEGF and NO secretions were also increased. Furthermore, in an in vivo model of hindlimb ischemia, HIF-1 alpha-transfected EPCs homed to the site of ischemia. A higher revascularization potential was also demonstrated by increased capillary density at the injury site. Our results revealed that endothelial progenitor cells ex vivo modification by hypoxia inducible factor-1 alpha gene transfection is feasible and may offer significant advantages in terms of EPC expansion and treatment efficacy.
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PMID:Angiogenesis by transplantation of HIF-1 alpha modified EPCs into ischemic limbs. 1754 46

Eleven subjects performed one-legged exercise four times per week for 5 wk. The subjects exercised one leg for 45 min with restricted blood flow (R leg), followed by exercise with the other leg at the same absolute workload with unrestricted blood flow (UR leg). mRNA and protein expression were measured in biopsies from the vastus lateralis muscle obtained at rest before the training period, after 10 days, and after 5 wk of training, as well as 120 min after the first and last exercise bouts. Basal Ang-2 and Tie-1 mRNA levels increased in both legs with training. The Ang-2-to-Ang-1 ratio increased to a greater extent in the R leg. The changes in Ang-2 mRNA were followed by similar changes at the protein level. In the R leg, VEGF-A mRNA expression responded transiently after acute exercise both before and after the 5-wk training program. Over the course of the exercise program, there was a concurrent increase in basal VEGF-A protein and VEGFR-2 mRNA in the R leg. Ki-67 mRNA showed a greater increase in the R leg and the protein was localized to the endothelial cells. In summary, the increased translation of VEGF-A is suggested to be caused by the short mRNA burst induced by each exercise bout. The concurrent increase in the Ang-2-to-Ang-1 ratio and the VEGF-expression combined with the higher level of Ki-67 mRNA in the R leg indicate that changes in these systems are of importance also in nonpathological angiogenic condition such as voluntary exercise in humans. It further establish that hypoxia/ischemia-related metabolic perturbation is likely to be involved as stimuli in this process in human skeletal muscle.
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PMID:The influence of physical training on the angiopoietin and VEGF-A systems in human skeletal muscle. 1756 64

Deficient angiogenesis after ischemia may contribute to worse outcomes of peripheral arterial disease in patients with diabetes mellitus (DM). Vascular endothelial growth factor (VEGF) and its receptors promote angiogenesis. We hypothesized that in peripheral arterial disease, maladaptive changes in VEGF ligand/receptor expression could account for impaired angiogenesis in DM. Skeletal muscle from diet-induced, type 2 diabetic (DM) and age-matched normal chow (NC)-fed mice was collected at baseline and 3 and 10 days after hindlimb ischemia and analyzed for expression of VEGF (n=10 per group), full-length VEGF receptor (VEGFR)-1, soluble VEGFR-1, and markers of downstream VEGF signaling (n=20 per group) using ELISA, reverse transcriptase-polymerase chain reaction, and Western blots. In the absence of ischemia, DM mice had increased VEGF (NC versus DM: 26.6+/-2.6 versus 53.5+/-8.8 pg/mg protein; P<0.05), decreased soluble and membrane-bound VEGFR-1 (NC versus DM: 1.44+/-0.30 versus 0.85+/-0.08 and 1.03+/-0.10 versus 0.72+/-0.10, respectively; P<0.05), decreased phospho-AKT/AKT and phospho-endothelial NO synthase/endothelial NO synthase (NC versus DM: 0.76+/-0.2 versus 0.38+/-0.1 and 0.36+/-0.06 versus 0.25+/-0.04, respectively; P<0.05), and no change in VEGFR-2. After ischemia, both DM and NC had comparable increases in VEGF-A. VEGFR-1 and soluble VEGFR-1 expression increased in both groups, but the fold increase was significantly greater in DM. These data demonstrate that soluble VEGFR-1, an angiogenesis inhibitor, is regulated in skeletal muscle by type 2 DM and ischemia. In the absence of ischemia, despite reductions in both soluble VEGFR-1 and VEGFR-1, VEGF ligand signaling is lower in DM compared with controls. After ischemia, maladaptive upregulation of these receptors further reduces the capacity of VEGF to induce an angiogenic response, which may provide a novel target for therapy.
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PMID:Impaired angiogenesis after hindlimb ischemia in type 2 diabetes mellitus: differential regulation of vascular endothelial growth factor receptor 1 and soluble vascular endothelial growth factor receptor 1. 1782 71

Early in mammalian development, the stem cell leukemia (SCL/TAL1) gene and its distinct 3' enhancer (SCL 3'En) specify bipotential progenitor cells that give rise to blood and endothelium, thus termed hemangioblasts. We have previously detected a minor population of SCL (+) cells in the postnatal kidney. Here, we demonstrate that cells expressing the SCL 3'En in the adult kidney are comprised of CD45+CD31- hematopoietic cells, CD45-CD31+ endothelial cells and CD45-CD31- interstitial cells. Creation of bone marrow chimeras of SCL 3'En transgenic mice into wild-type hosts shows that all three types of SCL 3'En-expressing cells in the adult kidney can originate from the bone marrow. Ischemia/reperfusion injury to the adult kidney of SCL 3'En transgenic mice results in the intrarenal elevation of SCL and FLK1 mRNA levels and of cells expressing hem-endothelial progenitor markers (CD45, CD34, c-Kit and FLK1). Furthermore, analysis of SCL 3'En in the ischemic kidneys reveals an increase in the abundance of SCL 3'En-expressing cells, predominantly within the CD45 (+) hematopoietic fraction and to a lesser extent in the CD45 (-) fraction. Our results suggest organ-injury-induced reactivation of bone marrow-derived hemangioblasts and possible local angioblastic progenitors expressing SCL and SCL 3'En.
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PMID:Organ-injury-induced reactivation of hemangioblastic precursor cells. 1789 90

Small airway fibrosis (bronchiolitis obliterans syndrome) is the primary obstacle to long-term survival following lung transplantation. Here, we show the importance of functional microvasculature in the prevention of epithelial loss and fibrosis due to rejection and for the first time, relate allograft microvascular injury and loss of tissue perfusion to immunotherapy-resistant rejection. To explore the role of alloimmune rejection and airway ischemia in the development of fibroproliferation, we used a murine orthotopic tracheal transplant model. We determined that transplants were reperfused by connection of recipient vessels to donor vessels at the surgical anastomosis site. Microcirculation through the newly formed vascular anastomoses appeared partially dependent on VEGFR2 and CXCR2 pathways. In the absence of immunosuppression, the microvasculature in rejecting allografts exhibited vascular complement deposition, diminished endothelial CD31 expression, and absent perfusion prior to the onset of fibroproliferation. Rejecting grafts with extensive endothelial cell injury were refractory to immunotherapy. After early microvascular loss, neovascularization was eventually observed in the membranous trachea, indicating a reestablishment of graft perfusion in established fibrosis. One implication of this study is that bronchial artery revascularization at the time of lung transplantation may decrease the risk of subsequent airway fibrosis.
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PMID:Microvascular destruction identifies murine allografts that cannot be rescued from airway fibrosis. 1806 23

Chronic hydrocephalus (CH) is a neurological disease characterized by increased cerebrospinal fluid volume and pressure that is often associated with impaired cognitive function. By and large, CH is a complex and heterogeneous cerebrospinal fluid (CSF) disorder where the exact site of brain insult is uncertain. Several mechanisms including neural compression, fiber stretch, and local or global hypoxia have been implicated in the underlying pathophysiology of CH. Specifically, the hippocampus, which plays a significant role in memory processing and is in direct contact with expanding CSF ventricles, may be involved. Using our model of chronic hydrocephalus, we quantified the density of vascular endothelial growth factor receptor 2 (VEGFR-2(+)) neurons, glial, endothelial cells, and blood vessels in hippocampal regions CA1, CA2-3, dentate gyrus and hilus using immunohistochemical and stereological methods. Density and %VEGFR-2(+) cell populations were estimated for CH animals (2-3 weeks vs. 12-16 weeks) and surgical controls (SC). Overall, we found approximately six- to eightfold increase in the cellular density of VEGFR-2(+) and more than double blood vessel density (BVd) in the hippocampus of CH compared with SC. There were no significant regional differences in VEGFR-2(+) cellular and BVd expression in the CH group. VEGFR-2(+) and BVds were significantly related to changes in CSF volume (P<or=0.05), and not intracranial pressure (ICP). The %VEGFR-2(+) was significantly greater in CH than SC (P<or=0.05), and was significantly correlated with BVd (P<or=0.05). These results showed that CH elicited a profound increase in VEGFR-2(+) in hippocampus that corresponded to increased BVd. It was unclear whether increased VEGFR-2(+) and blood vessel expression was related to focal compression alone or in combination with global ischemia/hypoxia conditions as previously described. These findings suggest that VEGFR-2 may play an adaptive role in angiogenesis after CH-induced hypoxia. Modulation of vascular endothelial growth factor/VEGFR-2(+) may be important in developing treatments for hypoxic conditions including hydrocephalus and other forms of cerebral ischemia.
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PMID:Chronic hydrocephalus-induced hypoxia: increased expression of VEGFR-2+ and blood vessel density in hippocampus. 1826 64


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