4 results on '"Nitzsche, Anja"'
Search Results
2. Endothelial S1P 1 Signaling Counteracts Infarct Expansion in Ischemic Stroke.
- Author
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Nitzsche A, Poittevin M, Benarab A, Bonnin P, Faraco G, Uchida H, Favre J, Garcia-Bonilla L, Garcia MCL, Léger PL, Thérond P, Mathivet T, Autret G, Baudrie V, Couty L, Kono M, Chevallier A, Niazi H, Tharaux PL, Chun J, Schwab SR, Eichmann A, Tavitian B, Proia RL, Charriaut-Marlangue C, Sanchez T, Kubis N, Henrion D, Iadecola C, Hla T, and Camerer E
- Subjects
- Animals, Blood-Brain Barrier drug effects, Blood-Brain Barrier pathology, Blood-Brain Barrier physiopathology, Cerebral Arteries drug effects, Cerebral Arteries pathology, Cerebral Arteries physiopathology, Cerebrovascular Circulation, Disease Models, Animal, Endothelial Cells pathology, Female, Infarction, Middle Cerebral Artery pathology, Infarction, Middle Cerebral Artery physiopathology, Infarction, Middle Cerebral Artery prevention & control, Ischemic Attack, Transient pathology, Ischemic Attack, Transient physiopathology, Ischemic Attack, Transient prevention & control, Ischemic Stroke pathology, Ischemic Stroke physiopathology, Ischemic Stroke prevention & control, Male, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Microcirculation, Neuroprotective Agents pharmacology, Signal Transduction, Sphingosine metabolism, Sphingosine-1-Phosphate Receptors agonists, Sphingosine-1-Phosphate Receptors genetics, Vascular Patency, Mice, Blood-Brain Barrier metabolism, Cerebral Arteries metabolism, Endothelial Cells metabolism, Infarction, Middle Cerebral Artery metabolism, Ischemic Attack, Transient metabolism, Ischemic Stroke metabolism, Lysophospholipids metabolism, Sphingosine analogs & derivatives, Sphingosine-1-Phosphate Receptors metabolism
- Abstract
Rationale: Cerebrovascular function is critical for brain health, and endogenous vascular protective pathways may provide therapeutic targets for neurological disorders. S1P (Sphingosine 1-phosphate) signaling coordinates vascular functions in other organs, and S1P
1 (S1P receptor-1) modulators including fingolimod show promise for the treatment of ischemic and hemorrhagic stroke. However, S1P1 also coordinates lymphocyte trafficking, and lymphocytes are currently viewed as the principal therapeutic target for S1P1 modulation in stroke., Objective: To address roles and mechanisms of engagement of endothelial cell S1P1 in the naive and ischemic brain and its potential as a target for cerebrovascular therapy., Methods and Results: Using spatial modulation of S1P provision and signaling, we demonstrate a critical vascular protective role for endothelial S1P1 in the mouse brain. With an S1P1 signaling reporter, we reveal that abluminal polarization shields S1P1 from circulating endogenous and synthetic ligands after maturation of the blood-neural barrier, restricting homeostatic signaling to a subset of arteriolar endothelial cells. S1P1 signaling sustains hallmark endothelial functions in the naive brain and expands during ischemia by engagement of cell-autonomous S1P provision. Disrupting this pathway by endothelial cell-selective deficiency in S1P production, export, or the S1P1 receptor substantially exacerbates brain injury in permanent and transient models of ischemic stroke. By contrast, profound lymphopenia induced by loss of lymphocyte S1P1 provides modest protection only in the context of reperfusion. In the ischemic brain, endothelial cell S1P1 supports blood-brain barrier function, microvascular patency, and the rerouting of blood to hypoperfused brain tissue through collateral anastomoses. Boosting these functions by supplemental pharmacological engagement of the endothelial receptor pool with a blood-brain barrier penetrating S1P1 -selective agonist can further reduce cortical infarct expansion in a therapeutically relevant time frame and independent of reperfusion., Conclusions: This study provides genetic evidence to support a pivotal role for the endothelium in maintaining perfusion and microvascular patency in the ischemic penumbra that is coordinated by S1P signaling and can be harnessed for neuroprotection with blood-brain barrier-penetrating S1P1 agonists.- Published
- 2021
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3. Sphingosine 1-phosphate-regulated transcriptomes in heterogenous arterial and lymphatic endothelium of the aorta.
- Author
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Engelbrecht E, Levesque MV, He L, Vanlandewijck M, Nitzsche A, Niazi H, Kuo A, Singh SA, Aikawa M, Holton K, Proia RL, Kono M, Pu WT, Camerer E, Betsholtz C, and Hla T
- Subjects
- Animals, Green Fluorescent Proteins metabolism, Mice, Mice, Transgenic, Sequence Analysis, RNA methods, Signal Transduction, Single-Cell Analysis methods, Sphingosine metabolism, Sphingosine-1-Phosphate Receptors genetics, Sphingosine-1-Phosphate Receptors metabolism, beta-Arrestins metabolism, Aorta metabolism, Endothelium, Lymphatic metabolism, Endothelium, Vascular metabolism, Lysophospholipids metabolism, Sphingosine analogs & derivatives, Transcriptome
- 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 NFκB 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/ß-arrestin coupling. In contrast, circulatory S1P-dependent S1PR1/ß-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., Competing Interests: EE, ML, LH, MV, AN, HN, AK, SS, MA, KH, RP, MK, WP, EC, CB No competing interests declared, TH received grant support from ONO Pharmaceuticals (2015-2018), has filed patent applications on ApoM, ApoM-Fc and HDL containing ApoM (US 62/545,629, PCT/US2018/000202, US 62/744,903, PCT/US2019/055831, US16/326,089, CA3034243, CN201780056922.6, JP 2019-530362, EPO 17851271.1), and has consulted for the following commercial entities: Astellas, Steptoe and Johnson, Gerson Lehrman Group Council, Janssen Research & Development, LLC, and Sun Pharma advanced research group (SPARC)
- Published
- 2020
- Full Text
- View/download PDF
4. Murine platelet production is suppressed by S1P release in the hematopoietic niche, not facilitated by blood S1P sensing.
- Author
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Niazi H, Zoghdani N, Couty L, Leuci A, Nitzsche A, Allende ML, Mariko B, Ishaq R, Aslan Y, Becker PH, Gazit SL, Poirault-Chassac S, Decouture B, Baudrie V, De Candia E, Kono M, Benarab A, Gaussem P, Tharaux PL, Chun J, Provot S, Debili N, Therond P, Proia RL, Bachelot-Loza C, and Camerer E
- Subjects
- Animals, Blood Platelets cytology, Lysophospholipids genetics, Megakaryocytes cytology, Mice, Mice, Knockout, Sphingosine genetics, Sphingosine metabolism, Sphingosine-1-Phosphate Receptors genetics, Sphingosine-1-Phosphate Receptors metabolism, Blood Platelets metabolism, Lysophospholipids metabolism, Megakaryocytes metabolism, Signal Transduction, Sphingosine analogs & derivatives, Stem Cell Niche, Thrombopoiesis
- Abstract
The bioactive lipid mediator sphingosine 1-phosphate (S1P) was recently assigned critical roles in platelet biology: whereas S1P
1 receptor-mediated S1P gradient sensing was reported to be essential for directing proplatelet extensions from megakaryocytes (MKs) toward bone marrow sinusoids, MK sphingosine kinase 2 (Sphk2)-derived S1P was reported to further promote platelet shedding through receptor-independent intracellular actions, and platelet aggregation through S1P1 Yet clinical use of S1P pathway modulators including fingolimod has not been associated with risk of bleeding or thrombosis. We therefore revisited the role of S1P in platelet biology in mice. Surprisingly, no reduction in platelet counts was observed when the vascular S1P gradient was ablated by impairing S1P provision to plasma or S1P degradation in interstitial fluids, nor when gradient sensing was impaired by S1pr1 deletion selectively in MKs. Moreover, S1P1 expression and signaling were both undetectable in mature MKs in situ, and MK S1pr1 deletion did not affect platelet aggregation or spreading. When S1pr1 deletion was induced in hematopoietic progenitor cells, platelet counts were instead significantly elevated. Isolated global Sphk2 deficiency was associated with thrombocytopenia, but this was not replicated by MK-restricted Sphk2 deletion and was reversed by compound deletion of either Sphk1 or S1pr2 , suggesting that this phenotype arises from increased S1P export and S1P2 activation secondary to redistribution of sphingosine to Sphk1. Consistent with clinical observations, we thus observe no essential role for S1P1 in facilitating platelet production or activation. Instead, S1P restricts megakaryopoiesis through S1P1 , and can further suppress thrombopoiesis through S1P2 when aberrantly secreted in the hematopoietic niche.- Published
- 2019
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