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)

The localized delivery of exogenous, angiogenic growth factors has become a promising alternative treatment of peripheral artery disease (PAD) and critical limb ischemia. In the present study, we describe the development of a novel controlled release vehicle to promote angiogenesis in a murine critical limb ischemic model. Ionic, gelatin-based hydrogels were prepared by the carbodiimide-mediated amidation reaction between the carboxyl groups of gelatin or poly-L-glutamic acid molecules and the amine groups of poly-L-lysine or gelatin molecules, respectively. The degree of swelling of the synthesized hydrogels was assessed as a function of EDC/NHS ratios and the pH of the equilibrating medium, while the release kinetic profile of basic fibroblast growth factor (FGF-2) was evaluated in human fibroblast cultures. The degree of swelling (DS) decreased from 26.5+/-1.7 to 18.5+/-2.4 as the EDC concentration varied from 0.75 to 2.5 mg/ml. Eighty percent of the FGF-2 was released at controlled rates from gelatin-polylysine (gelatin-PLL) and gelatin-polyglutamic acid (gelatin-PLG) hydrogel scaffolds over a period of 28 days. Cell adhesion studies revealed that the negatively charged surface of the gelatin-PLG hydrogels exhibited superior adhesion capabilities in comparison to gelatin-PLL and control gelatin surfaces. Laser Doppler perfusion imaging as well as CD31(+) capillary immunostaining demonstrated that the controlled release of FGF-2 from ionic gelatin-based hydrogels is superior in promoting angiogenesis in comparison to the bolus administration of the growth factor. Over 4 weeks, FGF-2 releasing gelatin-PLG hydrogels exhibited marked reperfusion with a Doppler ratio of 0.889 (+/-0.04) which was 69.3% higher than in the control groups.
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PMID:The effect of the controlled release of basic fibroblast growth factor from ionic gelatin-based hydrogels on angiogenesis in a murine critical limb ischemic model. 1732 Sep 47

Matrix metalloproteinases (MMPs) have been implicated in the process of neovascularization. However, the exact roles of individual MMPs in vessel formation are poorly understood. To study the putative role of MMP-2 in ischemia-induced neovascularization, a hindlimb ischemia model was applied to MMP-2(+/+) and MMP-2(-/-) mice. Serial laser Doppler blood-flow analysis revealed that the recovery of the ischemic/normal blood-flow ratio in MMP-2(-/-) young and old mice remained impaired throughout the follow-up period. At day 35, microangiography and anti-l-lectin immunohistochemical staining revealed lesser developed collateral vessels and capillary formation in both old and young MMP-2(-/-) mice compared with the age-matched MMP-2(+/+) mice. An aortic-ring culture assay showed a markedly impaired angiogenic response in MMP-2(-/-) mice, which was partially recovered by supplementation of the culture medium with recombinant MMP-2. Aorta-derived endothelial cells or bone marrow-derived endothelial progenitor cell (EPC)-like c-Kit(+) cells from MMP-2(-/-) showed marked impairment of invasive or/and proliferative abilities. At day 7, plasma and ischemic tissues of vascular endothelial growth factor protein were reduced in MMP-2(-/-). Flow cytometry showed that the numbers of EPC-like CD31(+)c-Kit(+) cells in peripheral blood markedly decreased in MMP-2-deficient mice. Transplantation of bone marrow-derived mononuclear cells from MMP-2(+/+) mice restored neovascularization in MMP-2(-/-) young mice. These data suggest that MMP-2 deficiency impairs ischemia-induced neovascularization through a reduction of endothelial cell and EPC invasive and/or proliferative activities and EPC mobilization.
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PMID:Mechanisms underlying the impairment of ischemia-induced neovascularization in matrix metalloproteinase 2-deficient mice. 1746 22

Junctional adhesion molecule-A (JAM-A) is a transmembrane protein expressed at tight junctions of endothelial and epithelial cells and on the surface of platelets and leukocytes. The role of JAM-A in leukocyte transmigration in vivo was directly investigated by intravital microscopy using both a JAM-A-neutralizing monoclonal antibody (mAb) (BV-11) and JAM-A-deficient (knockout [KO]) mice. Leukocyte transmigration (but not adhesion) through mouse cremasteric venules as stimulated by interleukin 1beta (IL-1beta) or ischemia/reperfusion (I/R) injury was significantly reduced in wild-type mice treated with BV-11 and in JAM-A KO animals. In contrast, JAM-A blockade/genetic deletion had no effect on responses elicited by leukotriene B(4) (LTB(4)) or platelet-activating factor (PAF). Furthermore, using a leukocyte transfer method and mice deficient in endothelial-cell JAM-A, evidence was obtained for the involvement of endothelial-cell JAM-A in leukocyte transmigration mediated by IL-1beta. Investigation of the functional relationship between JAM-A and PECAM-1 (CD31) determined that dual blockade/deletion of these proteins does not lead to an inhibitory effect greater than that seen with blockade/deletion of either molecule alone. The latter appeared to be due to the fact that JAM-A and PECAM-1 can act sequentially to mediate leukocyte migration through venular walls in vivo.
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PMID:JAM-A mediates neutrophil transmigration in a stimulus-specific manner in vivo: evidence for sequential roles for JAM-A and PECAM-1 in neutrophil transmigration. 1750 16

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

When harvesting microsurgical flaps, the main goals are to obtain as much tissue as possible based on a single vascular pedicle and a reliable vascularization of the entire flap. These aims being in contrast to each other, microsurgeons have been looking for an effective way to enhance skin and muscle perfusion in order to avoid partial flap loss in reconstructive surgery. In this study we demonstrate the efficacy of VEGF 165 delivered by an Adeno-Associated Virus (AAV) vector in two widely recognized rat flap models. In the rectus abdominis myocutaneous flap, intramuscular injection of AAV-VEGF reduced flap necrosis by 50%, while cutaneous delivery of the same amount of vector put down the epigastric flap's ischemia by >40%. Histological evidence of neoangiogenesis (enhanced presence of CD31-positive capillaries and alpha-Smooth Muscle Actin-positive arteriolae) confirmed the therapeutic effect of AAV-VEGF on flap perfusion.
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PMID:Improved survival of rat ischemic cutaneous and musculocutaneous flaps after VEGF gene transfer. 1759 44

Angiogenesis, the formation of new blood vessels, is a physiological response to tissue ischemia. Clinical evidence suggests that diabetic patients have endothelial dysfunction and impaired angiogenesis in response to ischemia. Here, we investigated the impact of diabetes on ischemia-induced collateral growth, and tested the hypothesis that peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist augments collateral flow to ischemic tissue. We conducted unilateral hindlimb ischemia surgery in KKAy mice. Blood flow recovery was markedly impaired in diabetic mice compared with that in wild-type mice as determined by laser Doppler imaging. Treatment of KKAy mice with pioglitazone partially restored the blood flow recovery. Anti-CD31 immunostaining revealed that pioglitazone also significantly improved the capillary density in ischemic limb muscle. Endothelial NO synthase (eNOS) activity was ameliorated in diabetic mice treated with pioglitazone as determined by vasorelaxation in response to acetylcholine. Pioglitazone normalized vascular endothelial growth factor (VEGF) protein levels, which was decreased in ischemic muscle of KKAy mice, and up-regulated eNOS phosphorylation at Ser-1177 and Akt phosphorylation at Ser-473 in ischemic muscle. Pioglitazone had no beneficial effects on blood flow recovery in diabetic mice treated with N(G)-nitro-l-arginine methyl ester (L-NAME). Our findings demonstrate that pioglitazone significantly ameliorates endothelial dysfunction and enhances blood flow recovery after tissue ischemia in diabetic mice. Activation of eNOS appears to be essential for pioglitazone to promote angiogenesis in ischemic tissue.
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PMID:Pioglitazone ameliorates endothelial dysfunction and restores ischemia-induced angiogenesis in diabetic mice. 1769 99

Cerebral ischemia induces angiogenesis within and around infarcted tissue. The protection of existing and growth of new blood vessels may contribute to a more favorable outcome. The present study assessed whether angiogenesis can be used as a marker for neurodegeneration/neuroprotection in a model of hypoxia-ischemia (HI). Increased CD31 immunoreactivity 7 days post-HI indicated increased angiogenesis compared to controls (P<0.001). Treatment with the GABA(A) receptor modulator, clomethiazole (CMZ; 414 mg/kg/day), normalized the level of angiogenesis compared to HI + saline (P<0.001). Conversely, the non-selective nitric oxide synthase (NOS) inhibitor, L-NAME (5 mg/kg/day), markedly decreased angiogenesis compared to controls (P<0.001). Circulating plasma levels of IL-1alpha, IL-1beta and GM-CSF were significantly elevated post-HI. CMZ treatment attenuated these increases while also stimulating IL-10 levels. L-NAME treatment did not alter IL-1alpha or IL-1beta levels, but decreased endogenous IL-10 levels and exacerbated the ischemic lesion (P<0.001). CMZ treatment has been shown to increase NOS levels, while L-NAME halted the HI-induced increase in NOS activity (P<0.001). We conclude that angiogenesis can be used as a marker of neurodegeneration/neuroprotection for cerebral HI and is correlated to NOS activity and circulating inflammatory mediators.
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PMID:Angiogenesis as a predictive marker of neurological outcome following hypoxia-ischemia. 1776 Nov 53

A novel population of tissue-resident endothelial precursors (TEPs) was isolated from small blood vessels in dermal, adipose, and skeletal muscle of mouse based on their ability to be grown as spheres. Cellular and molecular analyses of these cells revealed that they were highly related regardless of the tissue of origin and distinct from embryonic neural stem cells. Notably, TEPs did not express hematopoietic markers, but they expressed numerous characteristics of angiogenic precursors and their differentiated progeny, such as CD34, Flk-1, Tie-1, CD31, and vascular endothelial cadherin (VE-cadherin). TEPs readily differentiated into endothelial cells in newly formed vascular networks following transplantation into regenerating skeletal muscle. Taken together, these experiments suggest that TEPs represent a novel class of endothelial precursors that are closely associated with small blood vessels in muscle, adipose, and dermal tissue. This finding is of particular interest since it could bring new insight in cancer angiogenesis and collateral blood vessels developed following ischemia. Disclosure of potential conflicts of interest is found at the end of this article.
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PMID:Resident endothelial precursors in muscle, adipose, and dermis contribute to postnatal vasculogenesis. 1782 41

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


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