| 1. |
- Betsholtz, Christer, 1959, et al.
(author)
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Role of platelet-derived growth factor in mesangium development and vasculopathies: lessons from platelet-derived growth factor and platelet-derived growth factor receptor mutations in mice.
- 2004
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In: Current opinion in nephrology and hypertension. - 1062-4821. ; 13:1, s. 45-52
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Journal article (peer-reviewed)abstract
- PURPOSE OF REVIEW: The phenotypic consequences of null mutations in the platelet-derived growth factor-B and the platelet-derived growth factor beta-receptor genes in mice have demonstrated that these proteins play pivotal roles in the development of the vascular smooth muscle cell lineage, including pericytes and mesangial cells. RECENT FINDINGS: The lethality of these mutants has precluded analysis of the physiological and pathophysiological consequences of platelet-derived growth factor-B and platelet-derived growth factor beta-receptor deficiency in adults. This review summarizes and discusses recent data from certain tissue-specific and subtle mutations in the platelet-derived growth factor-B and platelet-derived growth factor beta-receptor genes that are compatible with postnatal viability in spite of severe developmental deficits in pericyte and mesangial cell recruitment. In the postnatal period, the animals studied developed a characteristic set of pathological changes to small blood vessels of the retina and the kidney glomerulus, which sheds light on the importance of pericytes and mesangial cells for vascular integrity and function after birth. SUMMARY: These microvascular abnormalities and their consequences bear a resemblance to diabetic microangiopathy and nephropathy. The platelet-derived growth factor-B and platelet-derived growth factor beta-receptor mutant mouse models, therefore, might serve as valuable tools in the dissection of some of the pathogenic events in diabetic microangiopathy.
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| 2. |
- Gallini, Radiosa, et al.
(author)
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PDGF-A and PDGF-B induces cardiac fibrosis in transgenic mice
- 2016
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In: Experimental Cell Research. - : Elsevier BV. - 0014-4827 .- 1090-2422. ; 349:2, s. 282-290
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Journal article (peer-reviewed)abstract
- Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) contribute to normal heart development. Deficient or abnormal expression of Pdgf and Pdgfr genes have a negative impact on cardiac development and function. The cellular effects of PDGFs in the hearts of Pdgf/Pdgfr mutants and the pathogenesis of the resulting abnormalities are poorly understood, but different PDGF isoforms induce varying effects. Here, we generated three new transgenic mouse types which complete a set of studies, where all different PDGF ligands have been expressed under the same heart specific alpha-myosin heavy chain promoter. Transgenic expression of the natural isoforms of Pdgfa and Pdgfb resulted in isoform specific fibrotic reactions and cardiac hypertrophy. Pdgfa overexpression resulted in a severe fibrotic reaction with up to 8-fold increase in cardiac size, leading to lethal cardiac failure within a few weeks after birth. In contrast, Pdgfb overexpression led to focal fibrosis and moderate cardiac hypertrophy. As PDGF-A and PDGF-B have different affinity for the two PDGF receptors, we analyzed the expression of the receptors and the histology of the fibrotic hearts. Our data suggest that the stronger fibrotic effect generated by Pdgfa overexpression was mediated by Pdgfrα in cardiac interstitial mesenchymal cells, i.e. the likely source of extracellular matrix depostion and fibrotic reaction. The apparent sensitivity of the heart to ectopic PDGFRα agonists supports a role for endogenous PDGFRα agonists in the pathogenesis of cardiac fibrosis. © 2016 The Authors
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| 3. |
- Lindblom, Per, 1974, et al.
(author)
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Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall.
- 2003
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In: Genes & development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 17:15, s. 1835-40
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Journal article (peer-reviewed)abstract
- Several platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) family members display C-terminal protein motifs that confer retention of the secreted factors within the pericellular space. To address the role of PDGF-B retention in vivo, we deleted the retention motif by gene targeting in mice. This resulted in defective investment of pericytes in the microvessel wall and delayed formation of the renal glomerulus mesangium. Long-term effects of lack of PDGF-B retention included severe retinal deterioration, glomerulosclerosis, and proteinuria. We conclude that retention of PDGF-B in microvessels is essential for proper recruitment and organization of pericytes and for renal and retinal function in adult mice.
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| 4. |
- Henningsson, Anna, et al.
(author)
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Human tick-borne encephalitis and characterization of virus from biting tick
- 2016
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In: Emerging Infectious Diseases. - : Centers for Disease Control and Prevention (CDC). - 1080-6040 .- 1080-6059. ; 22:8, s. 1485-1487
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Journal article (peer-reviewed)abstract
- We report a case of human tick-borne encephalitis (TBE) in which the TBE virus was isolated from the biting tick. Viral growth and sequence were characterized and compared with those of a reference strain. Virus isolation from ticks from patients with TBE may offer a new approach for studies of epidemiology and pathogenicity. © 2016, Centers for Disease Control and Prevention (CDC). All rights reserved.
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| 5. |
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| 6. |
- Lindblom, Jonas, 1974, et al.
(author)
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Model Based Spectrum Prediction
- 2000
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In: Proc. of the 2000 IEEE Workshop on Speech Coding. ; , s. 117-119
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Conference paper (peer-reviewed)
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| 7. |
- Lindblom, Per, 1974
(author)
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Role of extracellular retention of platelet-derived growth factor-B. Functions in development and disease
- 2003
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Doctoral thesis (other academic/artistic)abstract
- During development, the cell secretes growth and differentiation factors (GDFs) to the surrounding microenvironment. These factors are often key regulators of organogenesis and embryogenesis. Several GDFs carry sequences that mediate specific interaction with molecules of the extracellular matrix (ECM) that surrounds the cell. The deposition of factors in the matrix can theoretically result in (1) reservoirs of growth factors, (2) in spatially restricted action range of the factor or (3) in the critical growth factor concentrations or gradients needed for the factor to elicit specific cellular responses i.e. to act as a morphogen. So far, few attempts have been made to analyse the functional importance of GDF-ECM interactions. Several platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) family members display basic amino acid motifs at the C-terminus, which confer retention of the factor in the extracellular milieu surrounding the producing cell. To address the role of PDGF-B retention in vivo, we deleted the retention motif in mice by a gene targeting approach. This resulted in reduced recruitment and defective investment of pericytes in the micro-vessel wall, and in delayed formation of the glomerular mesangium. Long-term effects of lack of PDGF-B retention included reactive gliosis in the CNS, severe retinal detoriation, glomerulosclerosis and proteinuria. Several tumours express PDGF-B and the cognate receptor PDGFR-b. To investigate the effects of altered PDGF-B distribution in a pathological situation, we analysed the vasculature in a tumour model. In tumours transplanted to PDGF retention deficient mice, pericytes were fewer and partially detached, leading to significantly increased vessel diameter and haemorrhaging. Tumour specific over-expression of PDGF-B increased the pericyte density in both control and in PDGF-B retention deficient mice, but could not correct the defective pericyte integration in the vascular wall. To analyse developmental effects of PDGF over-expression, we generated transgenic mice that over-expressed different PDGF isoforms specifically in the heart. This caused pathological changes ranging from severe and generalised cardiac fibrosis and early postnatal lethality to focal fibrosis in the adult heart. Thus, PDGF signalling seems sufficient to induce cardiac fibrosis. In conclusion, the alteration of PDGF distribution or increased/decreased PDGF levels, have detrimental effects during development, as well as in the adult. The results point to an important role for PDGF in cancer and on retinal, glomerular and myocardial diseases.
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| 8. |
- Xian, Xiaojie, 1971, et al.
(author)
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Pericytes limit tumor cell metastasis.
- 2006
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In: The Journal of clinical investigation. - 0021-9738. ; 116:3, s. 642-51
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Journal article (peer-reviewed)abstract
- Previously we observed that neural cell adhesion molecule (NCAM) deficiency in beta tumor cells facilitates metastasis into distant organs and local lymph nodes. Here, we show that NCAM-deficient beta cell tumors grew leaky blood vessels with perturbed pericyte-endothelial cell-cell interactions and deficient perivascular deposition of ECM components. Conversely, tumor cell expression of NCAM in a fibrosarcoma model (T241) improved pericyte recruitment and increased perivascular deposition of ECM molecules. Together, these findings suggest that NCAM may limit tumor cell metastasis by stabilizing the microvessel wall. To directly address whether pericyte dysfunction increases the metastatic potential of solid tumors, we studied beta cell tumorigenesis in primary pericyte-deficient Pdgfb(ret/ret) mice. This resulted in beta tumor cell metastases in distant organs and local lymph nodes, demonstrating a role for pericytes in limiting tumor cell metastasis. These data support a new model for how tumor cells trigger metastasis by perturbing pericyte-endothelial cell-cell interactions.
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