| 1. |
- Fåhraeus, R, et al.
(författare)
-
Response to cAMP levels of the Epstein-Barr virus EBNA2-inducible LMP1 oncogene and EBNA2 inhibition of a PP1-like activity.
- 1994
-
Ingår i: The EMBO journal. - 0261-4189. ; 13:24, s. 6041-51
-
Tidskriftsartikel (refereegranskat)abstract
- The expression of the Epstein-Barr virus LMP1 oncogene is regulated by viral and non-viral factors in a tissue dependent fashion. The virus encoded transcription factor EBNA2 induces its expression in human B-cells. However, this induction also requires the contribution of cellular and/or other viral factors. In nasopharyngeal carcinoma cells and in cells from Hodgkin's lymphoma, LMP1 gene transcription is independent of viral products. Here we show that the effect of a factor binding to a cAMP responsive-like element (CRE) in the LMP1 gene transcription regulatory sequence (LRS) is essential for efficient promoter activity in the DG75 B-cell line and that elevation of cAMP levels in the cells induces LRS-derived CAT activity in a CRE dependent fashion. Incubation of two EBV-immortalized B-cell lines expressing endogenous EBNA2A with 8-Br cAMP increased the levels of the latency associated 66 kDa LMP1 within 2 h. Interestingly, LMP1 expression in DG75 cells conferred resistance to the inhibitory effect of 8-Br cAMP on cell proliferation. The protein phosphatase 1 and 2A (PP1 and PP2A, respectively) inhibitor okadaic acid also stimulated LRS-CAT activity in DG75 cells. EBNA2A from an EBV-immortalized B-cell line co-immunopurified with a PP1-like protein. An EBNA2A fragment spanning residues 324-436 fused to the GST protein specifically rescued a PP1/PP2A-like component from DG75 cell extracts. This GST-EBNA2A fusion product inhibited a PP1-like activity in nuclear extracts from these cells.
|
|
| 2. |
- Gaengel, K., et al.
(författare)
-
The Sphingosine-1-Phosphate Receptor S1PR1 Restricts Sprouting Angiogenesis by Regulating the Interplay between VE-Cadherin and VEGFR2
- 2012
-
Ingår i: Developmental Cell. - : Elsevier BV. - 1534-5807 .- 1878-1551. ; 23:3, s. 587-599
-
Tidskriftsartikel (refereegranskat)abstract
- Angiogenesis, the process by which new blood vessels arise from preexisting ones, is critical for embryonic development and is an integral part of many disease processes. Recent studies have provided detailed information on how angiogenic sprouts initiate, elongate, and branch, but less is known about how these processes cease. Here, we show that S1PR1, a receptor for the blood-borne bioactive lipid sphingosine-1-phosphate (S1P), is critical for inhibition of angiogenesis and acquisition of vascular stability. Loss of S1PR1 leads to increased endothelial cell sprouting and the formation of ectopic vessel branches. Conversely, S1PR1 signaling inhibits angiogenic sprouting and enhances cell-to-cell adhesion. This correlates with inhibition of vascular endothelial growth factor-A (VEGF-A)-induced signaling and stabilization of vascular endothelial (VE)-cadherin localization at endothelial junctions. Our data suggest that S1PR1 signaling acts as a vascular-intrinsic stabilization mechanism, protecting developing blood vessels against aberrant angiogenic responses.
|
|
| 3. |
|
|
| 4. |
- Rosengren, Anders, et al.
(författare)
-
Bone marrow transplantation stimulates pancreatic β-cell replication after tissue damage.
- 2009
-
Ingår i: Islets. - : Informa UK Limited. - 1938-2022 .- 1938-2014. ; 1:1, s. 10-18
-
Tidskriftsartikel (refereegranskat)abstract
- Bone marrow transplantation has been shown to normalize hyperglycemia but the mechanisms underlying pancreatic β-cell regeneration remain elusive. Here, we investigate the capacity of transplanted bone marrow cells to engraft into the pancreas, to adopt an endothelial cell phenotype and to stimulate β-cell regeneration after islet damage. Genetically marked whole bone marrow from Tie2-Cre/ZEG mice was transplanted into lethally irradiated wild-type mice. The fate of the transplanted cells, as well as blood glucose levels and β-cell mass dynamics, was investigated in normal and hyperglycemic recipient mice. Bone marrow transplantation significantly increased β-cell mass and reduced the hyperglycemia of mice subjected to β-cell damage by streptozotocin (STZ). This was associated with enhanced replication of pre-existing β-cells, proportional to the degree of β-cell damage, whereas no evidence was obtained for islet neogenesis. The engrafted bone marrow-derived cells in the pancreas showed little capacity to differentiate into blood vessel endothelium but retained a myeloid cell fate. By contrast, the transplantation evoked pronounced proliferation of recipient endothelial cells. These findings illuminate an important adjuvant function of transplanted bone marrow cells in both angiogenesis and β-cell regeneration. This may have interesting clinical implications, not least for human islet transplantation endeavours, where co-transplantation of islets with bone marrow cells might represent a simple means to improve islet survival and function.
|
|
| 5. |
- Rymo, Simin, 1959, et al.
(författare)
-
A Two-Way Communication between Microglial Cells and Angiogenic Sprouts Regulates Angiogenesis in Aortic Ring Cultures
- 2011
-
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Myeloid cells have been associated with physiological and pathological angiogenesis, but their exact functions in these processes remain poorly defined. Monocyte-derived tissue macrophages of the CNS, or microglial cells, invade the mammalian retina before it becomes vascularized. Recent studies correlate the presence of microglia in the developing CNS with vascular network formation, but it is not clear whether the effect is directly caused by microglia and their contact with the endothelium. Methodology/Principal Findings: We combined in vivo studies of the developing mouse retina with in vitro studies using the aortic ring model to address the role of microglia in developmental angiogenesis. Our in vivo analyses are consistent with previous findings that microglia are present at sites of endothelial tip-cell anastomosis, and genetic ablation of microglia caused a sparser vascular network associated with reduced number of filopodia-bearing sprouts. Addition of microglia in the aortic ring model was sufficient to stimulate vessel sprouting. The effect was independent of physical contact between microglia and endothelial cells, and could be partly mimicked using microglial cell-conditioned medium. Addition of VEGF-A promoted angiogenic sprouts of different morphology in comparison with the microglial cells, and inhibition of VEGF-A did not affect the microglia-induced angiogenic response, arguing that the proangiogenic factor(s) released by microglia is distinct from VEGF-A. Finally, microglia exhibited oriented migration towards the vessels in the aortic ring cultures. Conclusions/Significance: Microglia stimulate vessel sprouting in the aortic ring cultures via a soluble microglial-derived product(s), rather than direct contact with endothelial cells. The observed migration of microglia towards the growing sprouts suggests that their position near endothelial tip-cells could result from attractive cues secreted by the vessels. Our data reveals a two-way communication between microglia and vessels that depends on soluble factors and should extend the understanding of how microglia promote vascular network formation.
|
|
| 6. |
- Rymo, Simin, 1959
(författare)
-
On the stimulatory effect of microglial cells on angiogenesis
- 2011
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- ABSTRACT Angiogenesis, the process by which new vessels sprout from pre-existing vessels, is fundamental to development, tissue growth and repair. The main aim of this thesis was to investigate the role of microglia on angiogenesis. We adapted the rat ex vivo/in vitro aortic ring model to the mouse in a 3-D culture system. In paper I, we show that ablation of microglia in the retina leads to a poorly developed vascular network. The aortic ring model, supplied with microglia, demonstrated that microglia have a direct positive effect on angiogenic sprouting. The angiogenic effect was mediated by soluble factor/factors, and cell-cell contacts were not required. We also show that the microglia-derived angiogenic factor(s) is distinct from vascular endothelial growth factor-A. Moreover, the sprouting aortic ring induces oriented migration of microglia towards the aortic ring. In paper II, we analysed the microglia transcriptome. We found that microglia express known activators and inhibitors of angiogenesis that might have a role in retinal blood vessel development. The aortic ring system was also used as a complement to in vivo analyses to address the function of sphingosine-1- phosphate receptor 1 (S1P1) on angiogenesis (paper III). The results indicate that S1P1 is required within endothelial cells to counteract VEGFA- signalling and prevent endothelial hyper-sprouting. In paper IV, expression of green fluorescent protein in endothelial/hematopoietic cells using Tie2-Cre was used to mark transplanted bone marrow-derived cells. The study aimed to address if grafted bone marrow derived cells can differentiate into pancreatic β-cells in mice. The major part of the thesis concerns the establishment and use of the mouse aortic ring as a model for angiogenesis. Importantly, application of the system enabled us to identify a direct positive effect of microglia on angiogenesis and to test putative modifiers. This could be further pursued by microarray analyses. The presented work might therefore provide a platform for the identification of molecules that regulate angiogenesis. Key words: microglia, angiogenesis, aortic ring. ISBN: 978-91-628-8285-3
|
|
