Katja Issbrücker

Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Saxony, Germany

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Publications (8)43.69 Total impact

  • Cardiovascular Pathology 05/2004; 13(3):170-170. · 2.34 Impact Factor
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    ABSTRACT: Antimicrobial peptides are effector molecules of the innate immune system and contribute to host defense and regulation of inflammation. The human cathelicidin antimicrobial peptide LL-37/hCAP-18 is expressed in leukocytes and epithelial cells and secreted into wound and airway surface fluid. Here we show that LL-37 induces angiogenesis mediated by formyl peptide receptor-like 1 expressed on endothelial cells. Application of LL-37 resulted in neovascularization in the chorioallantoic membrane assay and in a rabbit model of hind-limb ischemia. The peptide directly activates endothelial cells, resulting in increased proliferation and formation of vessel-like structures in cultivated endothelial cells. Decreased vascularization during wound repair in mice deficient for CRAMP, the murine homologue of LL-37/hCAP-18, shows that cathelicidin-mediated angiogenesis is important for cutaneous wound neovascularization in vivo. Taken together, these findings demonstrate that LL-37/hCAP-18 is a multifunctional antimicrobial peptide with a central role in innate immunity by linking host defense and inflammation with angiogenesis and arteriogenesis.
    Journal of Clinical Investigation 07/2003; 111(11):1665-72. · 13.77 Impact Factor
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    ABSTRACT: In this study we have investigated the role of a specific corepressor of EGR-1, NAB2, to down-regulate vascular endothelial growth factor (VEGF)-induced gene expression in endothelial cells and to inhibit angiogenesis. Firstly, we show a reciprocal regulation of EGR-1 and NAB2 following VEGF treatment. During the initial phase EGR-1 is rapidly induced and NAB2 levels are down-regulated. This is followed by a reduction of EGR-1 and a concomitant increase of NAB2. Secondly, using the tissue factor gene as a readout for VEGF-induced and EGR-1-regulated gene expression we demonstrate that NAB2 can completely block VEGF-induced tissue factor reporter gene activity. Thirdly, by adenovirus-mediated expression we show that NAB2 inhibits up-regulation of tissue factor, VEGF receptor-1, and urokinase plasminogen activator mRNAs even when a combination of VEGF and bFGF is used for induction. In addition, NAB2 overexpression significantly reduced tubule and sprout formation in two different in vitro angiogenesis assays and largely prevented the invasion of cells and formation of vessel-like structures in the murine Matrigel model. These data suggest that NAB2 regulation represents a mechanism to guarantee transient EGR-1 activity following exposure of endothelial cells to VEGF and that NAB2 overexpression could be used to inhibit signals involved in the early phase of angiogenesis.
    Journal of Biological Chemistry 04/2003; 278(13):11433-40. · 4.60 Impact Factor
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    ABSTRACT: Two signaling receptors for vascular endothelial growth factor (VEGF) in the vasculature are known with not yet well-understood roles in collateral vessel growth (arteriogenesis). In this study, we examined the involvement of the two VEGF receptors in arteriogenesis. Therefore, we used the VEGF homologue placenta growth factor (PlGF), which only binds to VEGFR-1 and VEGF-E, which only recognizes VEGFR-2. These peptides were locally infused over 7 days after ligation of the femoral artery in the rabbit. Evaluation of collateral growth by determining collateral conductance and angiographic scores demonstrated that the VEGFR-1-specific PlGF contributed significantly more to arteriogenesis than the VEGFR-2 specific VEGF-E. The combination of VEGF-E and PlGF did not exceed the effect of PlGF alone, indicating that cooperation of the two VEGF receptors in endothelial cell signaling is not required for arteriogenesis. In an in vitro model of angiogenesis, VEGF and VEGF-E were comparably active, whereas PlGF displayed no activity when given alone and did not further increase the effects of VEGF or VEGF-E. However, PlGF was as potent as VEGF when monocyte activation was assessed by monitoring integrin surface expression. In addition, accumulation of activated monocytes/macrophages in the periphery of collateral vessels in PlGF-treated animals was observed. Furthermore, in monocyte-depleted animals, the ability of PlGF to enhance collateral growth in the rabbit model and to rescue impaired arteriogenesis in PlGF gene-deficient mice was abrogated. Together, these data indicate that the arteriogenic activity observed with the VEGFR-1-specific PlGF is caused by its monocyte-activating properties.
    Circulation Research 04/2003; 92(4):378-85. · 11.09 Impact Factor
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    ABSTRACT: Vascular endothelial growth factor (VEGF) is not only essential for vasculogenesis and angiogenesis but also is a potent inducer of vascular permeability. Although a dissection of the molecular pathways between angiogenesis- and vascular permeability-inducing properties would be desirable for the development of angiogenic and anti-angiogenic therapies, such mechanisms have not been identified yet. Here we provide evidence for a role of the p38 MAPK as the signaling molecule that separates these two processes. Inhibition of p38 MAPK activity enhances VEGF-induced angiogenesis in vitro and in vivo, a finding that was accompanied by prolonged Erk1/2 MAPK activation, increased endothelial survival, and plasminogen activation. Conversely, the same inhibitors abrogate VEGF-induced vascular permeability in vitro and in vivo. These dualistic properties of p38 MAPK are relevant not only for therapeutic angiogenesis but also for reducing edema formation and enhancing tissue repair in ischemic diseases.
    The FASEB Journal 03/2003; 17(2):262-4. · 5.48 Impact Factor
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    ABSTRACT: Vascular endothelial growth factor (VEGF-A) is the founding member of a family of angiogenic proteins with various binding abilities to three cognate VEGF receptors. Previously, a gene encoding from the genome of parapox orf virus (OV) with about 25% amino acid identity to mammalian VEGF-A was named VEGF-E and shown to bind and specifically activate the vascular endothelial growth factor receptor VEGFR-2 (KDR/flk-1). Here, we have generated a novel heparin-binding form of VEGF-E by introducing the heparin-domain of the human VEGF-A(165) splice variant into the viral VEGF-E protein. Recombinant heparin-binding VEGF-E (hbVEGF-E) is shown to stimulate proliferation and sprout formation of macro- and microvascular endothelial cells to a similar extent as the parental OV-VEGF-E but fails to activate peripheral mononuclear cells. However, hbVEGF-E is more potent in binding competition assays with primary human endothelial cells when compared to the OV-VEGF-E. This can be explained by our finding that binding of hbVEGF-E but not of parental OV-VEGF-E to the VEGFR-2 is strongly increased by the addition of neuropilin-1 (NP-1), a cognate co-receptor for VEGF-A. The engineered hbVEGF-E was compared with the VEGFR-1 selective and also heparin-binding form of placenta growth factor (PlGF-2) in vivo. Both heparin-binding homologues induced mobilization of endothelial progenitor cells from the bone marrow and gave rise to similar colony numbers of myeloic cells in a colony-forming assay. These findings suggest that both VEGFR-1 and VEGFR-2 are involved in stem cell mobilization.
    Angiogenesis 02/2003; 6(3):201-11. · 4.41 Impact Factor
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    ABSTRACT: Vascular endothelial growth factor (VEGF) is the major inducer of angiogenesis and vasculogenesis (Risau, 1997). It was isolated based on its ability to induce proliferation of endothelial cells but not fibroblasts (Leung et al., 1989). Based on this competency VEGF emerged as a highly good candidate as an angiogenesis-specific factor. Because VEGF is produced in response to hypoxia it describes a physiological mean to ablate the need of nutrients and oxygen by the induction of new blood vessels. In vitro, it induces several activities in endothelial cells, which are believed to be associated with angiogenesis, such as proliferation, survival and migration. But it also displays activities in endothelial cells, which were different from what was expected from an endothelial cell specific mitogen. VEGF can also induce vascular hyperpermeability, leading to its original description as vascular permeability factor (VPF) and turned out to be an inducer of tissue factor, the initiator of blood coagulation (Nemerson, 1988). In addition it is able to increase both the plasminogen activator and its inhibitor (Pepper et al., 1991). VEGF was found to cause release of von Willebrand factor from the Weibel-Palade bodies in endothelial cells and to increase the surface expression of P-selectin, two processes which comprise possible links to blood coagulation and inflammation, respectively. In consequence, the question arose whether VEGF would be a jack of all trades, comparable to another unspecific growth factor, fibroblast growth factor (FGF) (Clauss and Schaper, 2000). This point of view was enforced by the early finding that VEGF not only acts on endothelial cells but also on other cells. In this context monocytes were identified shortly after the discovery of VEGF as vascular endothelial growth factor (Clauss et al., 1990). In monocytes, VEGF induces chemotaxis, transmigration through endothelial monolayers, tissue factor and the inducible NO-Synthetase (Clauss, 1998). Furthermore, it was found to inhibit the differentiation to dendritic cells and to enforce the transition to endothelial cells (Gabrilovich et al., 1998). These diverse activities are not necessarily associated with angiogenesis. It should therefore be important to understand the mechanism of VEGF-elicited activities and, if possible to be able to distinguish VEGF-mediated activities on endothelial cells from those onto monocytes.
    Advances in Experimental Medicine and Biology 02/2003; 522:75-82. · 2.01 Impact Factor
  • FASEB Journal, v.17 (2002).