25 results on '"Nitzsche, Anja"'
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2. Maintien de la perfusion corticale par la sphingosine 1-phosphate lors de la phase aiguë de l’accident vasculaire cérébral ischémique
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Nitzsche, Anja, primary, Poittevin, Marine, additional, Benarab, Ammar, additional, Bonnin, Philippe, additional, and Camerer, Eric, additional
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- 2021
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3. Paladin is a phosphoinositide phosphatase regulating endosomal VEGFR2 signalling and angiogenesis
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Nitzsche, Anja, Pietilä, Riikka, Love, Dominic T., Testini, Chiara, Ninchoji, Takeshi, Smith, Ross O., Ekvärn, Elisabet, Larsson, Jimmy, Roche, Francis P., Egaña, Isabel, Jauhiainen, Suvi, Berger, Philipp, Claesson-Welsh, Lena, Hellström, Mats, Nitzsche, Anja, Pietilä, Riikka, Love, Dominic T., Testini, Chiara, Ninchoji, Takeshi, Smith, Ross O., Ekvärn, Elisabet, Larsson, Jimmy, Roche, Francis P., Egaña, Isabel, Jauhiainen, Suvi, Berger, Philipp, Claesson-Welsh, Lena, and Hellström, Mats
- Abstract
Cell signalling governs cellular behaviour and is therefore subject to tight spatiotemporal regulation. Signalling output is modulated by specialized cell membranes and vesicles which contain unique combinations of lipids and proteins. The phosphatidylinositol 4,5-bisphosphate (PI(4,5)P-2), an important component of the plasma membrane as well as other subcellular membranes, is involved in multiple processes, including signalling. However, which enzymes control the turnover of non-plasma membrane PI(4,5)P-2, and their impact on cell signalling and function at the organismal level are unknown. Here, we identify Paladin as a vascular PI(4,5)P-2 phosphatase regulating VEGFR2 endosomal signalling and angiogenesis. Paladin is localized to endosomal and Golgi compartments and interacts with vascular endothelial growth factor receptor 2 (VEGFR2) in vitro and in vivo. Loss of Paladin results in increased internalization of VEGFR2, over-activation of extracellular regulated kinase 1/2, and hypersprouting of endothelial cells in the developing retina of mice. These findings suggest that inhibition of Paladin, or other endosomal PI(4,5)P-2 phosphatases, could be exploited to modulate VEGFR2 signalling and angiogenesis, when direct and full inhibition of the receptor is undesirable., Shared first authorship: Anja Nitzsche, Riikka Pietilä and Dominic T Love
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- 2021
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4. Endothelial S1P 1 Signaling Counteracts Infarct Expansion in Ischemic Stroke
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Nitzsche, Anja, primary, Poittevin, Marine, additional, Benarab, Ammar, additional, Bonnin, Philippe, additional, Faraco, Giuseppe, additional, Uchida, Hiroki, additional, Favre, Julie, additional, Garcia-Bonilla, Lidia, additional, Garcia, Manuela C.L., additional, Léger, Pierre-Louis, additional, Thérond, Patrice, additional, Mathivet, Thomas, additional, Autret, Gwennhael, additional, Baudrie, Véronique, additional, Couty, Ludovic, additional, Kono, Mari, additional, Chevallier, Aline, additional, Niazi, Hira, additional, Tharaux, Pierre-Louis, additional, Chun, Jerold, additional, Schwab, Susan R., additional, Eichmann, Anne, additional, Tavitian, Bertrand, additional, Proia, Richard L., additional, Charriaut-Marlangue, Christiane, additional, Sanchez, Teresa, additional, Kubis, Nathalie, additional, Henrion, Daniel, additional, Iadecola, Costantino, additional, Hla, Timothy, additional, and Camerer, Eric, additional
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- 2021
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5. Sphingosine 1-phosphate-regulated transcriptomes in heterogenous arterial and lymphatic endothelium of the aorta
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Engelbrecht, Eric, Levesque, Michel, V, He, Liqun, Vanlandewijck, Michael, Nitzsche, Anja, Niazi, Hira, Kuo, Andrew, Singh, Sasha A., Aikawa, Masanori, Holton, Kristina, Proia, Richard L., Kono, Mari, Pu, William T., Camerer, Eric, Betsholtz, Christer, Hla, Timothy, Engelbrecht, Eric, Levesque, Michel, V, He, Liqun, Vanlandewijck, Michael, Nitzsche, Anja, Niazi, Hira, Kuo, Andrew, Singh, Sasha A., Aikawa, Masanori, Holton, Kristina, Proia, Richard L., Kono, Mari, Pu, William T., Camerer, Eric, Betsholtz, Christer, and Hla, Timothy
- Abstract
Despite the medical importance of G protein-coupled receptors (GPCRs), in vivo cellular heterogeneity of GPCR signaling and downstream transcriptional responses are not understood. We report the comprehensive characterization of transcriptomes (bulk and single-cell) and chromatin domains regulated by sphingosine 1-phosphate receptor-1 (S1PR1) in adult mouse aortic endothelial cells. First, S1PR1 regulates NF kappa B and nuclear glucocorticoid receptor pathways to suppress inflammation-related mRNAs. Second, S1PR1 signaling in the heterogenous endothelial cell (EC) subtypes occurs at spatially-distinct areas of the aorta. For example, a transcriptomically distinct arterial EC population at vascular branch points (aEC1) exhibits ligand-independent S1PR1/beta-arrestin coupling. In contrast, circulatory S1P-dependent S1PR1/beta-arrestin coupling was observed in non-branch point aEC2 cells that exhibit an inflammatory gene expression signature. Moreover, S1P/S1PR1 signaling regulates the expression of lymphangiogenic and inflammation-related transcripts in an adventitial lymphatic EC (LEC) population in a ligand-dependent manner. These insights add resolution to existing concepts of endothelial heterogeneity, GPCR signaling and S1P biology.
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- 2020
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6. Paladin is a phosphoinositide phosphatase regulating endosomal VEGFR2 signalling and angiogenesis
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Nitzsche, Anja, primary, Pietilä, Riikka, additional, Love, Dominic T, additional, Testini, Chiara, additional, Ninchoji, Takeshi, additional, Smith, Ross O, additional, Ekvärn, Elisabet, additional, Larsson, Jimmy, additional, Roche, Francis P, additional, Egaña, Isabel, additional, Jauhiainen, Suvi, additional, Berger, Philipp, additional, Claesson‐Welsh, Lena, additional, and Hellström, Mats, additional
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- 2020
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7. Sphingosine 1-phosphate-regulated transcriptomes in heterogenous arterial and lymphatic endothelium of the aorta
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Engelbrecht, Eric, primary, Levesque, Michel V, additional, He, Liqun, additional, Vanlandewijck, Michael, additional, Nitzsche, Anja, additional, Niazi, Hira, additional, Kuo, Andrew, additional, Singh, Sasha A, additional, Aikawa, Masanori, additional, Holton, Kristina, additional, Proia, Richard L, additional, Kono, Mari, additional, Pu, William T, additional, Camerer, Eric, additional, Betsholtz, Christer, additional, and Hla, Timothy, additional
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- 2020
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8. Murine platelet production is suppressed by S1P release in the hematopoietic niche, not facilitated by blood S1P sensing
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Niazi, Hira, primary, Zoghdani, Nesrine, additional, Couty, Ludovic, additional, Leuci, Alexandre, additional, Nitzsche, Anja, additional, Allende, Maria L., additional, Mariko, Boubacar, additional, Ishaq, Rameez, additional, Aslan, Yetki, additional, Becker, Pierre Hadrien, additional, Gazit, Salomé L., additional, Poirault-Chassac, Sonia, additional, Decouture, Benoit, additional, Baudrie, Veronique, additional, De Candia, Erica, additional, Kono, Mari, additional, Benarab, Ammar, additional, Gaussem, Pascale, additional, Tharaux, Pierre-Louis, additional, Chun, Jerold, additional, Provot, Sylvain, additional, Debili, Najet, additional, Therond, Patrice, additional, Proia, Richard L., additional, Bachelot-Loza, Christilla, additional, and Camerer, Eric, additional
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- 2019
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9. Female mice lacking Pald1 exhibit endothelial cell apoptosis and emphysema
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Egaña, Isabel, Kaito, Hiroshi, Nitzsche, Anja, Becker, Lore, Ballester-Lopez, Carolina, Niaudet, Colin, Petkova, Milena, Liu, Wei, Vanlandewijck, Michael, Vernaleken, Alexandra, Klopstock, Thomas, Fuchs, Helmut, Gailus-Durner, Valerie, Hrabe de Angelis, Martin, Rask-Andersen, Helge, Johansson, Henrik J., Lehtiö, Janne, He, Liqun, Yildirim, Ali Ö., and Hellström, Mats
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Cell- och molekylärbiologi ,Cell and Molecular Biology - Abstract
Paladin (Pald1, mKIAA1274 or x99384) was identified in screens for vascular-specific genes and is a putative phosphatase. Paladin has also been proposed to be involved in various biological processes such as insulin signaling, innate immunity and neural crest migration. To determine the role of paladin we have now characterized the Pald1 knock-out mouse in a broad array of behavioral, physiological and biochemical tests. Here, we show that female, but not male, Pald1 heterozygous and homozygous knock-out mice display an emphysema-like histology with increased alveolar air spaces and impaired lung function with an obstructive phenotype. In contrast to many other tissues where Pald1 is restricted to the vascular compartment, Pald1 is expressed in both the epithelial and mesenchymal compartments of the postnatal lung. However, in Pald1 knock-out females, there is a specific increase in apoptosis and proliferation of endothelial cells, but not in non-endothelial cells. This results in a transient reduction of endothelial cells in the maturing lung. Our data suggests that Pald1 is required during lung vascular development and for normal function of the developing and adult lung in a sex-specific manner. To our knowledge, this is the first report of a sex-specific effect on endothelial cell apoptosis. List of authors in thesis manuscript: Egaña I, Nitzsche A, Kaito H, Becker L, Garrett L, Niaudet C, Liu W, Vanlandewijck M, Larsson J, Hrabe de Angelis M, Fuchs H, Gailus-Durner V, Vernaleken A, Klopstock T, Hölter S M, Wurst W, Rask-Andersen H, German Mouse Clinic Consortium, Yildirim A Ö, Hellström M
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- 2017
10. The Role of Paladin in Endothelial Cell Signaling and Angiogenesis
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Nitzsche, Anja
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angiogenesis ,endothelium ,Cell- och molekylärbiologi ,Pald1 ,vascular permeability ,Cell and Molecular Biology ,lung ,phosphatase - Abstract
Angiogenesis, the formation of new blood vessels from a pre-existing vasculature, is crucial during development and for many diseases including cancer. Despite tremendous progress in the understanding of the angiogenic process, many aspects are still not fully elucidated. Several attempts have been made to identify novel genes involved in endothelial cell biology and angiogenesis. Here we focused on Pald1, a recently identified, vascular-enriched gene encoding paladin. Our in vitro studies indicate that paladin is a lipid phosphatase catalyzing dephosphorylation of phosphatidylinositol phosphates, a process essential for endocytosis and intracellular vesicle trafficking. We confirmed paladin’s vascular expression pattern and revealed a shift from a broad endothelial cell expression during development to an arterial mural cell-restricted expression in several vascular beds in adult mice. Paladin expression in the lung, however, was not restricted to the vasculature, but was also observed in pneumocytes and myofibroblasts. Lungs of female, but not male, Pald1 null mice displayed an obstructive lung phenotype with increased alveolar air sacs that were already apparent early in the alveolarization process. Only endothelial cells, but not other main lung cell types, were affected by loss of paladin. Endothelial cell number was reduced in 4-week old mice, possibly due to increased endothelial turnover in Pald1 deficient lungs. Vascular defects were also found in the retina. Loss of paladin led to reduced retinal vascular outgrowth accompanied by a hyperdense and hypersprouting vascular front. Downstream signaling of the major angiogenic driver, vascular endothelial growth factor receptor 2 (VEGFR2) was sustained in Pald1 null mice, and VEGFR2 degradation was impaired. Furthermore, paladin inhibited endothelial cell junction stability and loss of paladin led to reduced vascular permeability. Whether the differences in VEGFR2 signaling and adherens junction stability are connected remains to be fully explored. The newly identified lipid phosphatase activity of paladin and its specific effects on VEGFR2 signaling and adherens junction stability indicate that paladin may be controlling the endocytic pathway.
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- 2016
11. Paladin (X99384) is expressed in the vasculature and shifts from endothelial to vascular smooth muscle cells during mouse development
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Wallgard, Elisabet, Nitzsche, Anja, Larsson, Jimmy, Guo, Xiaoyuan, Dieterich, Lothar C., Dimberg, Anna, Olofsson, Tommie, Pontén, Fredrik C, Mäkinen, Taija, Kalen, Mattias, Hellström, Mats, Wallgard, Elisabet, Nitzsche, Anja, Larsson, Jimmy, Guo, Xiaoyuan, Dieterich, Lothar C., Dimberg, Anna, Olofsson, Tommie, Pontén, Fredrik C, Mäkinen, Taija, Kalen, Mattias, and Hellström, Mats
- Abstract
Background: Angiogenesis is implicated in many pathological conditions. The role of the proteins involved remains largely unknown, and few vascular-specific drug targets have been discovered. Previously, in a screen for angiogenesis regulators, we identified Paladin (mouse: X99384, human: KIAA1274), a protein containing predicted S/T/Y phosphatase domains. Results: We present a mouse knockout allele for Paladin with a beta-galactosidase reporter, which in combination with Paladin antibodies demonstrate that Paladin is expressed in the vasculature. During mouse embryogenesis, Paladin is primarily expressed in capillary and venous endothelial cells. In adult mice Paladin is predominantly expressed in arterial pericytes and vascular smooth muscle cells. Paladin also displays vascular-restricted expression in human brain, astrocytomas, and glioblastomas. Conclusions: Paladin, a novel putative phosphatase, displays a dynamic expression pattern in the vasculature. During embryonic stages it is broadly expressed in endothelial cells, while in the adult it is selectively expressed in arterial smooth muscle cells.
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- 2012
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12. Gamma-Secretase Inhibitor Treatment Promotes VEGF-A-Driven Blood Vessel Growth and Vascular Leakage but Disrupts Neovascular Perfusion
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Kalén, Mattias, Heikura, Tommi, Karvinen, Henna, Nitzsche, Anja, Weber, Holger, Esser, Norbert, Yla-Herttuala, Seppo, Hellström, Mats, Kalén, Mattias, Heikura, Tommi, Karvinen, Henna, Nitzsche, Anja, Weber, Holger, Esser, Norbert, Yla-Herttuala, Seppo, and Hellström, Mats
- Abstract
The Notch signaling pathway is essential for normal development due to its role in control of cell differentiation, proliferation and survival. It is also critically involved in tumorigenesis and cancer progression. A key enzyme in the activation of Notch signaling is the gamma-secretase protein complex and therefore, gamma-secretase inhibitors (GSIs)originally developed for Alzheimer's disease-are now being evaluated in clinical trials for human malignancies. It is also clear that Notch plays an important role in angiogenesis driven by Vascular Endothelial Growth Factor A (VEGF-A)-a process instrumental for tumor growth and metastasis. The effect of GSIs on tumor vasculature has not been conclusively determined. Here we report that Compound X (CX), a GSI previously reported to potently inhibit Notch signaling in vitro and in vivo, promotes angiogenic sprouting in vitro and during developmental angiogenesis in mice. Furthermore, CX treatment suppresses tumor growth in a mouse model of renal carcinoma, leads to the formation of abnormal vessels and an increased tumor vascular density. Using a rabbit model of VEGF-A-driven angiogenesis in skeletal muscle, we demonstrate that CX treatment promotes abnormal blood vessel growth characterized by vessel occlusion, disrupted blood flow, and increased vascular leakage. Based on these findings, we propose a model for how GSIs and other Notch inhibitors disrupt tumor blood vessel perfusion, which might be useful for understanding this new class of anti-cancer agents.
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- 2011
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13. RAD21 Cooperates with Pluripotency Transcription Factors in the Maintenance of Embryonic Stem Cell Identity
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Buchholz, Frank, Nitzsche, Anja, Paszkowski-Rogacz, Maciej, Matarese, Filomena, Janssen-Megens, Eva M., Hubner, Nina C., Schulz, Herbert, de Vries, Ingrid, Ding, Li, Huebner, Norbert, Mann, Matthias, Stunnenberg, Hendrik G., Buchholz, Frank, Nitzsche, Anja, Paszkowski-Rogacz, Maciej, Matarese, Filomena, Janssen-Megens, Eva M., Hubner, Nina C., Schulz, Herbert, de Vries, Ingrid, Ding, Li, Huebner, Norbert, Mann, Matthias, and Stunnenberg, Hendrik G.
- Abstract
For self-renewal, embryonic stem cells (ESCs) require the expression of specific transcription factors accompanied by a particular chromosome organization to maintain a balance between pluripotency and the capacity for rapid differentiation. However, how transcriptional regulation is linked to chromosome organization in ESCs is not well understood. Here we show that the cohesin component RAD21 exhibits a functional role in maintaining ESC identity through association with the pluripotency transcriptional network. ChIP-seq analyses of RAD21 reveal an ESC specific cohesin binding pattern that is characterized by CTCF independent co-localization of cohesin with pluripotency related transcription factors Oct4, Nanog, Sox2, Esrrb and Klf4. Upon ESC differentiation, most of these binding sites disappear and instead new CTCF independent RAD21 binding sites emerge, which are enriched for binding sites of transcription factors implicated in early differentiation. Furthermore, knock-down of RAD21 causes expression changes that are similar to expression changes after Nanog depletion, demonstrating the functional relevance of the RAD21 - pluripotency transcriptional network association. Finally, we show that Nanog physically interacts with the cohesin or cohesin interacting proteins STAG1 and WAPL further substantiating this association. Based on these findings we propose that a dynamic placement of cohesin by pluripotency transcription factors contributes to a chromosome organization supporting the ESC expression program.
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- 2011
14. RAD21 Cooperates with Pluripotency Transcription Factors in the Maintenance of Embryonic Stem Cell Identity
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Nitzsche, Anja, primary, Paszkowski-Rogacz, Maciej, additional, Matarese, Filomena, additional, Janssen-Megens, Eva M., additional, Hubner, Nina C., additional, Schulz, Herbert, additional, de Vries, Ingrid, additional, Ding, Li, additional, Huebner, Norbert, additional, Mann, Matthias, additional, Stunnenberg, Hendrik G., additional, and Buchholz, Frank, additional
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- 2011
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15. Gamma-Secretase Inhibitor Treatment Promotes VEGF-A-Driven Blood Vessel Growth and Vascular Leakage but Disrupts Neovascular Perfusion
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Kalén, Mattias, primary, Heikura, Tommi, additional, Karvinen, Henna, additional, Nitzsche, Anja, additional, Weber, Holger, additional, Esser, Norbert, additional, Ylä-Herttuala, Seppo, additional, and Hellström, Mats, additional
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- 2011
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16. A Genome-Scale RNAi Screen for Oct4 Modulators Defines a Role of the Paf1 Complex for Embryonic Stem Cell Identity
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Ding, Li, primary, Paszkowski-Rogacz, Maciej, additional, Nitzsche, Anja, additional, Slabicki, Mikolaj Michal, additional, Heninger, Anne-Kristin, additional, Vries, Ingrid de, additional, Kittler, Ralf, additional, Junqueira, Magno, additional, Shevchenko, Andrej, additional, Schulz, Herbert, additional, Hubner, Norbert, additional, Doss, Michael Xavier, additional, Sachinidis, Agapios, additional, Hescheler, Juergen, additional, Iacone, Roberto, additional, Anastassiadis, Konstantinos, additional, Stewart, A. Francis, additional, Pisabarro, M. Teresa, additional, Caldarelli, Antonio, additional, Poser, Ina, additional, Theis, Mirko, additional, and Buchholz, Frank, additional
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- 2009
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17. RNase H-mediated retrovirus destruction in vivo triggered by oligodeoxynucleotides
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Matzen, Kathrin, primary, Elzaouk, Lina, additional, Matskevich, Alexey A, additional, Nitzsche, Anja, additional, Heinrich, Jochen, additional, and Moelling, Karin, additional
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- 2007
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18. Paladin (Pald1) regulates endothelial sprouting, VE-cadherin junction stability and vascular permeability
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Nitzsche, Anja, Testini, Chiara, Ekvärn, Elisabet, Larsson, Jimmy, Bentley, Katie, Philippides, Andrew, Roche, Francis P., Egaña, Isabel, Smith, Ross, Hellberg, Carina, Ballmer-Hofer, Kurt, Hellström, Mats, Nitzsche, Anja, Testini, Chiara, Ekvärn, Elisabet, Larsson, Jimmy, Bentley, Katie, Philippides, Andrew, Roche, Francis P., Egaña, Isabel, Smith, Ross, Hellberg, Carina, Ballmer-Hofer, Kurt, and Hellström, Mats
19. Paladin (Pald1) regulates endothelial sprouting, VE-cadherin junction stability and vascular permeability
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Nitzsche, Anja, Testini, Chiara, Ekvärn, Elisabet, Larsson, Jimmy, Bentley, Katie, Philippides, Andrew, Roche, Francis P., Egaña, Isabel, Smith, Ross, Hellberg, Carina, Ballmer-Hofer, Kurt, Berger, Philipp, Hellström, Mats, Nitzsche, Anja, Testini, Chiara, Ekvärn, Elisabet, Larsson, Jimmy, Bentley, Katie, Philippides, Andrew, Roche, Francis P., Egaña, Isabel, Smith, Ross, Hellberg, Carina, Ballmer-Hofer, Kurt, Berger, Philipp, and Hellström, Mats
20. Anthrax toxins regulate pain signaling and can deliver molecular cargoes into ANTXR2(+) DRG sensory neurons
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Yang, Nicole J., Isensee, Joerg, Neel, Dylan, V, Quadros, Andreza U., Zhang, Han-Xiong Bear, Lauzadis, Justas, Liu, Sai Man, Shiers, Stephanie, Belu, Andreea, Palan, Shilpa, Marlin, Sandra, Maignel, Jacquie, Kennedy-Curran, Angela, Tong, Victoria S., Moayeri, Mahtab, Roederer, Pascal, Nitzsche, Anja, Lu, Mike, Pentelute, Bradley L., Bruestle, Oliver, Tripathi, Vineeta, Foster, Keith A., Price, Theodore J., Collier, R. John, Leppla, Stephen H., Puopolo, Michelino, Bean, Bruce P., Cunha, Thiago M., Hucho, Tim, Chiu, Isaac M., Yang, Nicole J., Isensee, Joerg, Neel, Dylan, V, Quadros, Andreza U., Zhang, Han-Xiong Bear, Lauzadis, Justas, Liu, Sai Man, Shiers, Stephanie, Belu, Andreea, Palan, Shilpa, Marlin, Sandra, Maignel, Jacquie, Kennedy-Curran, Angela, Tong, Victoria S., Moayeri, Mahtab, Roederer, Pascal, Nitzsche, Anja, Lu, Mike, Pentelute, Bradley L., Bruestle, Oliver, Tripathi, Vineeta, Foster, Keith A., Price, Theodore J., Collier, R. John, Leppla, Stephen H., Puopolo, Michelino, Bean, Bruce P., Cunha, Thiago M., Hucho, Tim, and Chiu, Isaac M.
- Abstract
Discovering that nociceptive sensory neurons express the receptor for anthrax toxin, Yang et al. show that anthrax toxin can induce potent analgesia in mice and facilitate the delivery of potentially analgesic cargo proteins into nociceptive neurons. Bacterial products can act on neurons to alter signaling and function. In the present study, we found that dorsal root ganglion (DRG) sensory neurons are enriched for ANTXR2, the high-affinity receptor for anthrax toxins. Anthrax toxins are composed of protective antigen (PA), which binds to ANTXR2, and the protein cargoes edema factor (EF) and lethal factor (LF). Intrathecal administration of edema toxin (ET (PA + EF)) targeted DRG neurons and induced analgesia in mice. ET inhibited mechanical and thermal sensation, and pain caused by formalin, carrageenan or nerve injury. Analgesia depended on ANTXR2 expressed by Na(v)1.8(+) or Advillin(+) neurons. ET modulated protein kinase A signaling in mouse sensory and human induced pluripotent stem cell-derived sensory neurons, and attenuated spinal cord neurotransmission. We further engineered anthrax toxins to introduce exogenous protein cargoes, including botulinum toxin, into DRG neurons to silence pain. Our study highlights interactions between a bacterial toxin and nociceptors, which may lead to the development of new pain therapeutics.
21. Anthrax toxins regulate pain signaling and can deliver molecular cargoes into ANTXR2(+) DRG sensory neurons
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Yang, Nicole J., Isensee, Joerg, Neel, Dylan, V, Quadros, Andreza U., Zhang, Han-Xiong Bear, Lauzadis, Justas, Liu, Sai Man, Shiers, Stephanie, Belu, Andreea, Palan, Shilpa, Marlin, Sandra, Maignel, Jacquie, Kennedy-Curran, Angela, Tong, Victoria S., Moayeri, Mahtab, Roederer, Pascal, Nitzsche, Anja, Lu, Mike, Pentelute, Bradley L., Bruestle, Oliver, Tripathi, Vineeta, Foster, Keith A., Price, Theodore J., Collier, R. John, Leppla, Stephen H., Puopolo, Michelino, Bean, Bruce P., Cunha, Thiago M., Hucho, Tim, Chiu, Isaac M., Yang, Nicole J., Isensee, Joerg, Neel, Dylan, V, Quadros, Andreza U., Zhang, Han-Xiong Bear, Lauzadis, Justas, Liu, Sai Man, Shiers, Stephanie, Belu, Andreea, Palan, Shilpa, Marlin, Sandra, Maignel, Jacquie, Kennedy-Curran, Angela, Tong, Victoria S., Moayeri, Mahtab, Roederer, Pascal, Nitzsche, Anja, Lu, Mike, Pentelute, Bradley L., Bruestle, Oliver, Tripathi, Vineeta, Foster, Keith A., Price, Theodore J., Collier, R. John, Leppla, Stephen H., Puopolo, Michelino, Bean, Bruce P., Cunha, Thiago M., Hucho, Tim, and Chiu, Isaac M.
- Abstract
Discovering that nociceptive sensory neurons express the receptor for anthrax toxin, Yang et al. show that anthrax toxin can induce potent analgesia in mice and facilitate the delivery of potentially analgesic cargo proteins into nociceptive neurons. Bacterial products can act on neurons to alter signaling and function. In the present study, we found that dorsal root ganglion (DRG) sensory neurons are enriched for ANTXR2, the high-affinity receptor for anthrax toxins. Anthrax toxins are composed of protective antigen (PA), which binds to ANTXR2, and the protein cargoes edema factor (EF) and lethal factor (LF). Intrathecal administration of edema toxin (ET (PA + EF)) targeted DRG neurons and induced analgesia in mice. ET inhibited mechanical and thermal sensation, and pain caused by formalin, carrageenan or nerve injury. Analgesia depended on ANTXR2 expressed by Na(v)1.8(+) or Advillin(+) neurons. ET modulated protein kinase A signaling in mouse sensory and human induced pluripotent stem cell-derived sensory neurons, and attenuated spinal cord neurotransmission. We further engineered anthrax toxins to introduce exogenous protein cargoes, including botulinum toxin, into DRG neurons to silence pain. Our study highlights interactions between a bacterial toxin and nociceptors, which may lead to the development of new pain therapeutics.
22. Zonation, ligand and dose dependence of S1PR1 signalling in blood and lymphatic vasculature.
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Del Gaudio I, Nitzsche A, Boyé K, Bonnin P, Poulet M, Nguyen TQ, Couty L, Ha HTT, Nguyen DT, Cazenave-Gassiot A, Ben Alaya K, Thérond P, Chun J, Wenk MR, Proia RL, Henrion D, Nguyen LN, Eichmann A, and Camerer E
- Abstract
Aims: Circulating levels of sphingosine 1-phosphate (S1P), an HDL-associated ligand for endothelial cell (EC) protective S1P receptor-1 (S1PR1), are reduced in disease states associated with endothelial dysfunction. Yet as S1PR1 has high affinity for S1P and can be activated by ligand-independent mechanisms and EC-autonomous S1P production, it is unclear if relative reductions in circulating S1P impact endothelial function. It is also unclear how EC S1PR1 insufficiency, whether induced by ligand deficiency or by S1PR1-directed immunosuppressive therapy, affects different vascular subsets., Methods and Results: We here fine-map the zonation of S1PR1 signalling in the murine blood and lymphatic vasculature, superimpose cell type-specific and relative deficiencies in S1P production to define ligand source- and dose-dependence, and correlate receptor engagement to essential functions. In naïve blood vessels, despite broad expression, EC S1PR1 engagement was restricted to resistance-size arteries, lung capillaries and high-endothelial venules (HEV). Similar zonation was observed for albumin extravasation in EC S1PR1 deficient mice, and brain extravasation was reproduced with arterial EC-selective S1pr1 deletion. In lymphatic EC, S1PR1 engagement was high in collecting vessels and lymph nodes and low in terminal capillaries that drain tissue fluids. While EC S1P production sustained S1PR1 signaling in lymphatics and HEV, hematopoietic cells provided ∼90% of plasma S1P and sustained signaling in resistance arteries and lung capillaries. S1PR1 signaling and endothelial function were both surprisingly sensitive to reductions in plasma S1P with apparent saturation around 50% of normal levels. S1PR1 engagement did not depend on sex or age, but modestly increased in arteries in hypertension and diabetes. Sphingosine kinase (Sphk)-2 deficiency also increased S1PR1 engagement selectively in arteries, which could be attributed to Sphk1-dependent S1P release from perivascular macrophages., Conclusions: This study highlights vessel subtype-specific S1PR1 functions and mechanisms of engagement and supports the relevance of S1P as circulating biomarker for endothelial function., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
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- 2024
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23. [Endothelial sphingosine 1-phosphate signaling maintains perfusion of the cerebral cortex in ischemic stroke].
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Nitzsche A, Poittevin M, Benarab A, Bonnin P, and Camerer E
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- Cerebral Cortex, Humans, Perfusion, Brain Ischemia, Ischemic Stroke, Lysophospholipids, Sphingosine analogs & derivatives, Stroke
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- 2021
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24. Paladin is a phosphoinositide phosphatase regulating endosomal VEGFR2 signalling and angiogenesis.
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Nitzsche A, Pietilä R, Love DT, Testini C, Ninchoji T, Smith RO, Ekvärn E, Larsson J, Roche FP, Egaña I, Jauhiainen S, Berger P, Claesson-Welsh L, and Hellström M
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- Animals, Endothelial Cells metabolism, Mice, Phosphatidylinositol 4,5-Diphosphate, Signal Transduction, Neovascularization, Physiologic, Phosphoinositide Phosphatases, Phosphoprotein Phosphatases, Vascular Endothelial Growth Factor Receptor-2 genetics, Vascular Endothelial Growth Factor Receptor-2 metabolism
- Abstract
Cell signalling governs cellular behaviour and is therefore subject to tight spatiotemporal regulation. Signalling output is modulated by specialized cell membranes and vesicles which contain unique combinations of lipids and proteins. The phosphatidylinositol 4,5-bisphosphate (PI(4,5)P
2 ), an important component of the plasma membrane as well as other subcellular membranes, is involved in multiple processes, including signalling. However, which enzymes control the turnover of non-plasma membrane PI(4,5)P2 , and their impact on cell signalling and function at the organismal level are unknown. Here, we identify Paladin as a vascular PI(4,5)P2 phosphatase regulating VEGFR2 endosomal signalling and angiogenesis. Paladin is localized to endosomal and Golgi compartments and interacts with vascular endothelial growth factor receptor 2 (VEGFR2) in vitro and in vivo. Loss of Paladin results in increased internalization of VEGFR2, over-activation of extracellular regulated kinase 1/2, and hypersprouting of endothelial cells in the developing retina of mice. These findings suggest that inhibition of Paladin, or other endosomal PI(4,5)P2 phosphatases, could be exploited to modulate VEGFR2 signalling and angiogenesis, when direct and full inhibition of the receptor is undesirable., (© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)- Published
- 2021
- Full Text
- View/download PDF
25. Female mice lacking Pald1 exhibit endothelial cell apoptosis and emphysema.
- Author
-
Egaña I, Kaito H, Nitzsche A, Becker L, Ballester-Lopez C, Niaudet C, Petkova M, Liu W, Vanlandewijck M, Vernaleken A, Klopstock T, Fuchs H, Gailus-Durner V, Hrabe de Angelis M, Rask-Andersen H, Johansson HJ, Lehtiö J, He L, Yildirim AÖ, and Hellström M
- Subjects
- Animals, Disease Models, Animal, Embryo, Mammalian, Emphysema genetics, Female, Heterozygote, Humans, Lung blood supply, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Phosphoprotein Phosphatases genetics, Sex Factors, Apoptosis physiology, Emphysema pathology, Endothelial Cells pathology, Endothelium, Vascular growth & development, Phosphoprotein Phosphatases metabolism
- Abstract
Paladin (Pald1, mKIAA1274 or x99384) was identified in screens for vascular-specific genes and is a putative phosphatase. Paladin has also been proposed to be involved in various biological processes such as insulin signaling, innate immunity and neural crest migration. To determine the role of paladin we have now characterized the Pald1 knock-out mouse in a broad array of behavioral, physiological and biochemical tests. Here, we show that female, but not male, Pald1 heterozygous and homozygous knock-out mice display an emphysema-like histology with increased alveolar air spaces and impaired lung function with an obstructive phenotype. In contrast to many other tissues where Pald1 is restricted to the vascular compartment, Pald1 is expressed in both the epithelial and mesenchymal compartments of the postnatal lung. However, in Pald1 knock-out females, there is a specific increase in apoptosis and proliferation of endothelial cells, but not in non-endothelial cells. This results in a transient reduction of endothelial cells in the maturing lung. Our data suggests that Pald1 is required during lung vascular development and for normal function of the developing and adult lung in a sex-specific manner. To our knowledge, this is the first report of a sex-specific effect on endothelial cell apoptosis.
- Published
- 2017
- Full Text
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