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| 2. |
- Wang, Yingdi, et al.
(författare)
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Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis.
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 465:7297
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Tidskriftsartikel (refereegranskat)abstract
- In development, tissue regeneration or certain diseases, angiogenic growth leads to the expansion of blood vessels and the lymphatic vasculature. This involves endothelial cell proliferation as well as angiogenic sprouting, in which a subset of cells, termed tip cells, acquires motile, invasive behaviour and extends filopodial protrusions. Although it is already appreciated that angiogenesis is triggered by tissue-derived signals, such as vascular endothelial growth factor (VEGF) family growth factors, the resulting signalling processes in endothelial cells are only partly understood. Here we show with genetic experiments in mouse and zebrafish that ephrin-B2, a transmembrane ligand for Eph receptor tyrosine kinases, promotes sprouting behaviour and motility in the angiogenic endothelium. We link this pro-angiogenic function to a crucial role of ephrin-B2 in the VEGF signalling pathway, which we have studied in detail for VEGFR3, the receptor for VEGF-C. In the absence of ephrin-B2, the internalization of VEGFR3 in cultured cells and mutant mice is defective, which compromises downstream signal transduction by the small GTPase Rac1, Akt and the mitogen-activated protein kinase Erk. Our results show that full VEGFR3 signalling is coupled to receptor internalization. Ephrin-B2 is a key regulator of this process and thereby controls angiogenic and lymphangiogenic growth.
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| 3. |
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| 4. |
- Adams, Jonathan, et al.
(författare)
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Editorial
- 2015
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Ingår i: Medieval Sermon Studies. - 1366-0691 .- 1749-6276. ; 59:1, s. 1-1
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 5. |
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| 6. |
- Alonso-Mori, Roberto, et al.
(författare)
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Energy-dispersive X-ray emission spectroscopy using an X-ray free-electron laser in a shot-by-shot mode
- 2012
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 109:47, s. 19103-19107
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Tidskriftsartikel (refereegranskat)abstract
- The ultrabright femtosecond X-ray pulses provided by X-ray free-electron lasers open capabilities for studying the structure and dynamics of a wide variety of systems beyond what is possible with synchrotron sources. Recently, this probe-before-destroy approach has been demonstrated for atomic structure determination by serial X-ray diffraction of microcrystals. There has been the question whether a similar approach can be extended to probe the local electronic structure by X-ray spectroscopy. To address this, we have carried out femtosecond X-ray emission spectroscopy (XES) at the Linac Coherent Light Source using redox-active Mn complexes. XES probes the charge and spin states as well as the ligand environment, critical for understanding the functional role of redox-active metal sites. K beta(1,3) XES spectra of Mn-II and Mn-2(III,IV) complexes at room temperature were collected using a wavelength dispersive spectrometer and femtosecond X-ray pulses with an individual dose of up to > 100 MGy. The spectra were found in agreement with undamaged spectra collected at low dose using synchrotron radiation. Our results demonstrate that the intact electronic structure of redox active transition metal compounds in different oxidation states can be characterized with this shot-by-shot method. This opens the door for studying the chemical dynamics of metal catalytic sites by following reactions under functional conditions. The technique can be combined with X-ray diffraction to simultaneously obtain the geometric structure of the overall protein and the local chemistry of active metal sites and is expected to prove valuable for understanding the mechanism of important metalloproteins, such as photosystem II.
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| 7. |
- Alvarez, Alberto, et al.
(författare)
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Cdc42 is required in mural cells for proper patterning of the retinal vasculature
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Mural cells constitute the outer lining of blood vessels. They are known as pericytes in the capillary network and referred to as smooth muscle cells (SMC) around arteries and veins. Despite their ubiquity, their contribution to vascular morphogenesis remains obscure. In this work, we investigated the role of Cdc42 in mural cells in vivo, using the developing mouse retina as a model. We find that, during postnatal development, Cdc42 is required in both, pericytes and smooth muscle cells to maintain proper cell morphology, coverage and distribution. During retinal angiogenesis, Cdc42-depleted pericytes lag behind the sprouting front, at least in part due to decreased proliferation. Consequently, capillaries at the sprouting front remain pericyte deprived and are prone to increased vascular leakage. In addition, arteries and arterioles deviate from their normal growth directions and trajectory. While in the adult retina, mural cell coverage normalizes and pericytes adopt a normal morphology, smooth muscle cell morphologies remain abnormal and arteriolar branching angles are markedly reduced. Our findings demonstrate that Cdc42 is required for mural cell proliferation, morphology and distribution and suggest that mural cells are essential for normal vascular morphogenesis of the developing retinal vasculature.
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| 8. |
- Bazigou, Eleni, et al.
(författare)
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Integrin-alpha9 is required for fibronectin matrix assembly during lymphatic valve morphogenesis.
- 2009
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Ingår i: Developmental Cell. - : Elsevier BV. - 1534-5807 .- 1878-1551. ; 17:2
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Tidskriftsartikel (refereegranskat)abstract
- Dysfunction of lymphatic valves underlies human lymphedema, yet the process of valve morphogenesis is poorly understood. Here, we show that during embryogenesis, lymphatic valve leaflet formation is initiated by upregulation of integrin-alpha9 expression and deposition of its ligand fibronectin-EIIIA (FN-EIIIA) in the extracellular matrix. Endothelial cell-specific deletion of Itga9 (encoding integrin-alpha9) in mouse embryos results in the development of rudimentary valve leaflets characterized by disorganized FN matrix, short cusps, and retrograde lymphatic flow. Similar morphological and functional defects are observed in mice lacking the EIIIA domain of FN. Mechanistically, we demonstrate that in primary human lymphatic endothelial cells, the integrin-alpha9-EIIIA interaction directly regulates FN fibril assembly, which is essential for the formation of the extracellular matrix core of valve leaflets. Our findings reveal an important role for integrin-alpha9 signaling during lymphatic valve morphogenesis and implicate it as a candidate gene for primary lymphedema caused by valve defects.
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| 9. |
- Borg, Mikael, et al.
(författare)
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Experimental and theoretical surface core-level shifts of aluminum (100) and (111)
- 2004
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Ingår i: Physical Review B. - 1550-235X. ; 69
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Tidskriftsartikel (refereegranskat)abstract
- The surface core-level shifts of Al(111) and Al(100) have been measured using high-resolution core-level photoemission spectroscopy and calculated using density functional theory (DFT). For Al(100), the 2p core-level shift of the first (second) layer was determined to be –75 meV (+20 meV) from experiment and –71 meV (+20 meV) from the DFT calculations. For Al(111), the corresponding values are –27 meV (0 meV) from experiment and –14 meV (–) from the DFT calculations. Core-level splittings caused by the low-symmetry crystal fields at the (111) and (100) surfaces have also been studied. These splittings turn out to be much smaller than previously reported provided proper care is taken of the influence of the core hole screening and of core–valence exchange beyond the DFT level. Finally, the experimental Al 2p line shape was found to contain structure caused by a sharp no-phonon line and a broad and weak phonon replica.
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| 10. |
- Bravi, Luca, et al.
(författare)
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Sulindac metabolites decrease cerebrovascular malformations in CCM3-knockout mice
- 2015
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 112:27, s. 8421-8426
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral cavernous malformation (CCM) is a disease of the central nervous system causing hemorrhage-prone multiple lumen vascular malformations and very severe neurological consequences. At present, the only recommended treatment of CCM is surgical. Because surgery is often not applicable, pharmacological treatment would be highly desirable. We describe here a murine model of the disease that develops after endothelial-cell-selective ablation of the CCM3 gene. We report an early, cell-autonomous, Wnt-receptor-independent stimulation of beta-catenin transcription activity in CCM3-deficient endothelial cells both in vitro and in vivo and a triggering of a beta-catenin-driven transcription program that leads to endothelial-tomesenchymal transition. TGF-beta/BMP signaling is then required for the progression of the disease. We also found that the anti-inflammatory drugs sulindac sulfide and sulindac sulfone, which attenuate beta-catenin transcription activity, reduce vascular malformations in endothelial CCM3-deficient mice. This study opens previously unidentified perspectives for an effective pharmacological therapy of intracranial vascular cavernomas.
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