| 1. |
- Abramsson, Alexandra, 1973, et al.
(författare)
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Defective N-sulfation of heparan sulfate proteoglycans limits PDGF-BB binding and pericyte recruitment in vascular development
- 2007
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Ingår i: GENES & DEVELOPMENT. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 21:3, s. 316-331
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Tidskriftsartikel (refereegranskat)abstract
- During vascular development, endothelial platelet-derived growth factor B (PDGF-B) is critical for pericyte recruitment. Deletion of the conserved C-terminal heparin-binding motif impairs PDGF-BB retention and pericyte recruitment in vivo, suggesting a potential role for heparan sulfate (HS) in PDGF-BB function during vascular development. We studied the participation of HS chains in pericyte recruitment using two mouse models with altered HS biosynthesis. Reduction of N-sulfation due to deficiency in N-deacetylase/N-sulfotransferase-1 attenuated PDGF-BB binding in vitro, and led to pericyte detachment and delayed pericyte migration in vivo. Reduced N-sulfation also impaired PDGF-BB signaling and directed cell migration, but not proliferation. In contrast, HS from glucuronyl C5-epimerase mutants, which is extensively N- and 6-O-sulfated, but lacks 2-O-sulfated L-iduronic acid residues, retained PDGF-BB in vitro, and pericyte recruitment in vivo was only transiently delayed. These observations were supported by in vitro characterization of the structural features in HS important for PDGF-BB binding. We conclude that pericyte recruitment requires HS with sufficiently extended and appropriately spaced N-sulfated domains to retain PDGF-BB and activate PDGF receptor β (PDGFRβ) signaling, whereas the detailed sequence of monosaccharide and sulfate residues does not appear to be important for this interaction.
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| 2. |
- Bentley, Katie, et al.
(författare)
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The role of differential VE-cadherin dynamics in cell rearrangement during angiogenesis
- 2014
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Ingår i: Nature Cell Biology. - : Springer Science and Business Media LLC. - 1465-7392 .- 1476-4679. ; 16:4, s. 309-321
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Tidskriftsartikel (refereegranskat)abstract
- Endothelial cells show surprising cell rearrangement behaviour during angiogenic sprouting; however, the underlying mechanisms and functional importance remain unclear. By combining computational modelling with experimentation, we identify that Notch/VEGFR-regulated differential dynamics of VE-cadherin junctions drive functional endothelial cell rearrangements during sprouting. We propose that continual flux in Notch signalling levels in individual cells results in differential VE-cadherin turnover and junctional-cortex protrusions, which powers differential cell movement. In cultured endothelial cells, Notch signalling quantitatively reduced junctional VE-cadherin mobility. In simulations, only differential adhesion dynamics generated long-range position changes, required for tip cell competition and stalk cell intercalation. Simulation and quantitative image analysis on VE-cadherin junctional patterning in vivo identified that differential VE-cadherin mobility is lost under pathological high VEGF conditions, in retinopathy and tumour vessels. Our results provide a mechanistic concept for how cells rearrange during normal sprouting and how rearrangement switches to generate abnormal vessels in pathologies.
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| 3. |
- Betsholtz, Christer, 1959, et al.
(författare)
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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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Ingår i: Current opinion in nephrology and hypertension. - 1062-4821. ; 13:1, s. 45-52
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Tidskriftsartikel (refereegranskat)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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| 4. |
- Claesson-Welsh, Lena, et al.
(författare)
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Introduction to the ECR special angiogenesis issue
- 2013
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Ingår i: Experimental Cell Research. - : Elsevier BV. - 0014-4827 .- 1090-2422. ; 319:9, s. 1239-1239
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 5. |
- Cruys, Bert, et al.
(författare)
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Glycolytic regulation of cell rearrangement in angiogenesis
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- During vessel sprouting, endothelial cells (ECs) dynamically rearrange positions in the sprout to compete for the tip position. We recently identified a key role for the glycolytic activator PFKFB3 in vessel sprouting by regulating cytoskeleton remodelling, migration and tip cell competitiveness. It is, however, unknown how glycolysis regulates EC rearrangement during vessel sprouting. Here we report that computational simulations, validated by experimentation, predict that glycolytic production of ATP drives EC rearrangement by promoting filopodia formation and reducing intercellular adhesion. Notably, the simulations correctly predicted that blocking PFKFB3 normalizes the disturbed EC rearrangement in high VEGF conditions, as occurs during pathological angiogenesis. This interdisciplinary study integrates EC metabolism in vessel sprouting, yielding mechanistic insight in the control of vessel sprouting by glycolysis, and suggesting anti-glycolytic therapy for vessel normalization in cancer and non-malignant diseases.
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| 6. |
- de Oliveira, Marta Bastos, et al.
(författare)
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Vasohibin 1 selectively regulates secondary sprouting and lymphangiogenesis in the zebrafish trunk
- 2021
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Ingår i: Development. - : COMPANY BIOLOGISTS LTD. - 0950-1991 .- 1477-9129. ; 148:4
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies have shown that Vasohibin 1 (Vash1) is stimulated by VEGFs in endothelial cells and that its overexpression interferes with angiogenesis in vivo. Recently, Vash1 was found to mediate tubulin detyrosination, a post-translational modification that is implicated in many cell functions, such as cell division. Here, we used the zebrafish embryo to investigate the cellular and subcellular mechanisms of Vash1 on endothelial microtubules during formation of the trunk vasculature. We show that microtubules within venous-derived secondary sprouts are strongly and selectively detyrosinated in comparison with other endothelial cells, and that this difference is lost upon vash1 knockdown. Vash1 depletion in zebrafish specifically affected secondary sprouting from the posterior cardinal vein, increasing endothelial cell divisions and cell number in the sprouts. We show that altering secondary sprout numbers and structure upon Vash1 depletion leads to defective lymphatic vessel formation and ectopic lymphatic progenitor specification in the zebrafish trunk.
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| 7. |
- Enge, Maria, 1970, et al.
(författare)
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Endothelium-specific platelet-derived growth factor-B ablation mimics diabetic retinopathy.
- 2002
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Ingår i: The EMBO journal. - : Wiley. - 0261-4189 .- 1460-2075. ; 21:16, s. 4307-16
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Tidskriftsartikel (refereegranskat)abstract
- Loss of pericytes from the capillary wall is a hallmark of diabetic retinopathy, however, the pathogenic significance of this phenomenon is unclear. In previous mouse gene knockout models leading to pericyte deficiency, prenatal lethality has so far precluded analysis of postnatal consequences in the retina. We now report that endothelium-restricted ablation of platelet-derived growth factor-B generates viable mice with extensive inter- and intra-individual variation in the density of pericytes throughout the CNS. We found a strong inverse correlation between pericyte density and the formation of a range of retinal microvascular abnormalities strongly reminiscent of those seen in diabetic humans. Proliferative retinopathy invariably developed when pericyte density was <50% of normal. Our data suggest that a reduction of the pericyte density is sufficient to cause retinopathy in mice, implying that pericyte loss may also be a causal pathogenic event in human diabetic retinopathy.
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| 8. |
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| 9. |
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| 10. |
- Hellström, Mats, et al.
(författare)
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Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis.
- 2007
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 445:7129, s. 776-80
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Tidskriftsartikel (refereegranskat)abstract
- In sprouting angiogenesis, specialized endothelial tip cells lead the outgrowth of blood-vessel sprouts towards gradients of vascular endothelial growth factor (VEGF)-A. VEGF-A is also essential for the induction of endothelial tip cells, but it is not known how single tip cells are selected to lead each vessel sprout, and how tip-cell numbers are determined. Here we present evidence that delta-like 4 (Dll4)-Notch1 signalling regulates the formation of appropriate numbers of tip cells to control vessel sprouting and branching in the mouse retina. We show that inhibition of Notch signalling using gamma-secretase inhibitors, genetic inactivation of one allele of the endothelial Notch ligand Dll4, or endothelial-specific genetic deletion of Notch1, all promote increased numbers of tip cells. Conversely, activation of Notch by a soluble jagged1 peptide leads to fewer tip cells and vessel branches. Dll4 and reporters of Notch signalling are distributed in a mosaic pattern among endothelial cells of actively sprouting retinal vessels. At this location, Notch1-deleted endothelial cells preferentially assume tip-cell characteristics. Together, our results suggest that Dll4-Notch1 signalling between the endothelial cells within the angiogenic sprout serves to restrict tip-cell formation in response to VEGF, thereby establishing the adequate ratio between tip and stalk cells required for correct sprouting and branching patterns. This model offers an explanation for the dose-dependency and haploinsufficiency of the Dll4 gene, and indicates that modulators of Dll4 or Notch signalling, such as gamma-secretase inhibitors developed for Alzheimer's disease, might find usage as pharmacological regulators of angiogenesis.
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