Ellen Knevels

Publications (5)71.51 Total impact

• Article: TRPA1 underlies a sensing mechanism for O2.

  Nobuaki Takahashi, Tomoyuki Kuwaki, Shigeki Kiyonaka, Tomohiro Numata, Daisuke Kozai, Yusuke Mizuno, Shinichiro Yamamoto, Shinji Naito, Ellen Knevels, Peter Carmeliet, Toru Oga, Shuji Kaneko, Seiji Suga, Toshiki Nokami, Jun-ichi Yoshida, Yasuo Mori
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  ABSTRACT: Oxygen (O(2)) is a prerequisite for cellular respiration in aerobic organisms but also elicits toxicity. To understand how animals cope with the ambivalent physiological nature of O(2), it is critical to elucidate the molecular mechanisms responsible for O(2) sensing. Here our systematic evaluation of transient receptor potential (TRP) cation channels using reactive disulfides with different redox potentials reveals the capability of TRPA1 to sense O(2). O(2) sensing is based upon disparate processes: whereas prolyl hydroxylases (PHDs) exert O(2)-dependent inhibition on TRPA1 activity in normoxia, direct O(2) action overrides the inhibition via the prominent sensitivity of TRPA1 to cysteine-mediated oxidation in hyperoxia. Unexpectedly, TRPA1 is activated through relief from the same PHD-mediated inhibition in hypoxia. In mice, disruption of the Trpa1 gene abolishes hyperoxia- and hypoxia-induced cationic currents in vagal and sensory neurons and thereby impedes enhancement of in vivo vagal discharges induced by hyperoxia and hypoxia. The results suggest a new O(2)-sensing mechanism mediated by TRPA1.
  Nature Chemical Biology 08/2011; 7(10):701-11. · 14.69 Impact Factor
• Source

  Available from: Carmen Ruiz de Almodovar Egea

  Article: VEGF modulates NMDA receptors activity in cerebellar granule cells through Src-family kinases before synapse formation.

  Claire Meissirel, Carmen Ruiz de Almodovar, Ellen Knevels, Cathy Coulon, Naura Chounlamountri, Inmaculada Segura, Pierre de Rossi, Stefan Vinckier, Kristof Anthonis, Bérangère Deléglise, [......], Pieter Vanden Berghe, Ludo Van den Bosch, Wim Robberecht, Alain Chédotal, Salvatore Oliviero, Mieke Dewerchin, Dietmar Schmucker, Nicole Thomasset, Paul Salin, Peter Carmeliet
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  ABSTRACT: NMDA type glutamate receptors (NMDARs) are best known for their role in synaptogenesis and synaptic plasticity. Much less is known about their developmental role before neurons form synapses. We report here that VEGF, which promotes migration of granule cells (GCs) during postnatal cerebellar development, enhances NMDAR-mediated currents and Ca(2+) influx in immature GCs before synapse formation. The VEGF receptor Flk1 forms a complex with the NMDAR subunits NR1 and NR2B. In response to VEGF, the number of Flk1/NR2B coclusters on the cell surface increases. Stimulation of Flk1 by VEGF activates Src-family kinases, which increases tyrosine phosphorylation of NR2B. Inhibition of Src-family kinases abolishes the VEGF-dependent NR2B phosphorylation and amplification of NMDAR-mediated currents and Ca(2+) influx in GCs. These findings identify VEGF as a modulator of NMDARs before synapse formation and highlight a link between an activity-independent neurovascular guidance cue (VEGF) and an activity-regulated neurotransmitter receptor (NMDAR).
  Proceedings of the National Academy of Sciences 08/2011; 108(33):13782-7. · 9.68 Impact Factor
• Source

  Available from: Inmaculada Segura

  Article: VEGF mediates commissural axon chemoattraction through its receptor Flk1.

  Carmen Ruiz de Almodovar, Pierre J Fabre, Ellen Knevels, Cathy Coulon, Inmaculada Segura, Patrick C G Haddick, Liesbeth Aerts, Nicolas Delattin, Geraldine Strasser, Won-Jong Oh, [......], Stefan Vinckier, Jody Haigh, Coralie Fouquet, Chengua Gu, Kari Alitalo, Valerie Castellani, Marc Tessier-Lavigne, Alain Chedotal, Frederic Charron, Peter Carmeliet
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  ABSTRACT: Growing axons are guided to their targets by attractive and repulsive cues. In the developing spinal cord, Netrin-1 and Shh guide commissural axons toward the midline. However, the combined inhibition of their activity in commissural axon turning assays does not completely abrogate turning toward floor plate tissue, suggesting that additional guidance cues are present. Here we show that the prototypic angiogenic factor VEGF is secreted by the floor plate and is a chemoattractant for commissural axons in vitro and in vivo. Inactivation of Vegf in the floor plate or of its receptor Flk1 in commissural neurons causes axon guidance defects, whereas Flk1 blockade inhibits turning of axons to VEGF in vitro. Similar to Shh and Netrin-1, VEGF-mediated commissural axon guidance requires the activity of Src family kinases. Our results identify VEGF and Flk1 as a novel ligand/receptor pair controlling commissural axon guidance.
  Neuron 06/2011; 70(5):966-78. · 14.74 Impact Factor
• Source

  Available from: Jo Van Ginderachter

  Article: HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF.

  Charlotte Rolny, Massimiliano Mazzone, Sònia Tugues, Damya Laoui, Irja Johansson, Cathy Coulon, Mario Leonardo Squadrito, Inmaculada Segura, Xiujuan Li, Ellen Knevels, [......], Sabine Wyns, Erik Larsson, Ian Buysschaert, Johan Botling, Uwe Himmelreich, Jo A Van Ginderachter, Michele De Palma, Mieke Dewerchin, Lena Claesson-Welsh, Peter Carmeliet
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  ABSTRACT: Polarization of tumor-associated macrophages (TAMs) to a proangiogenic/immune-suppressive (M2-like) phenotype and abnormal, hypoperfused vessels are hallmarks of malignancy, but their molecular basis and interrelationship remains enigmatic. We report that the host-produced histidine-rich glycoprotein (HRG) inhibits tumor growth and metastasis, while improving chemotherapy. By skewing TAM polarization away from the M2- to a tumor-inhibiting M1-like phenotype, HRG promotes antitumor immune responses and vessel normalization, effects known to decrease tumor growth and metastasis and to enhance chemotherapy. Skewing of TAM polarization by HRG relies substantially on downregulation of placental growth factor (PlGF). Besides unveiling an important role for TAM polarization in tumor vessel abnormalization, and its regulation by HRG/PlGF, these findings offer therapeutic opportunities for anticancer and antiangiogenic treatment.
  Cancer cell 01/2011; 19(1):31-44. · 25.29 Impact Factor
• Source

  Available from: David Gall

  Article: Matrix-binding vascular endothelial growth factor (VEGF) isoforms guide granule cell migration in the cerebellum via VEGF receptor Flk1.

  Carmen Ruiz de Almodovar, Cathy Coulon, Paul Antoine Salin, Ellen Knevels, Naura Chounlamountri, Koen Poesen, Karlien Hermans, Diether Lambrechts, Katie Van Geyte, Joke Dhondt, [......], Marie-Françoise Belin, Serge Schiffmann, Paul Van Hecke, Bernard Gallez, Stefan Vinckier, Alain Chédotal, Jérôme Honnorat, Nicole Thomasset, Peter Carmeliet, Claire Meissirel
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  ABSTRACT: Vascular endothelial growth factor (VEGF) regulates angiogenesis, but also has important, yet poorly characterized roles in neuronal wiring. Using several genetic and in vitro approaches, we discovered a novel role for VEGF in the control of cerebellar granule cell (GC) migration from the external granule cell layer (EGL) toward the Purkinje cell layer (PCL). GCs express the VEGF receptor Flk1, and are chemoattracted by VEGF, whose levels are higher in the PCL than EGL. Lowering VEGF levels in mice in vivo or ectopic VEGF expression in the EGL ex vivo perturbs GC migration. Using GC-specific Flk1 knock-out mice, we provide for the first time in vivo evidence for a direct chemoattractive effect of VEGF on neurons via Flk1 signaling. Finally, using knock-in mice expressing single VEGF isoforms, we show that pericellular deposition of matrix-bound VEGF isoforms around PC dendrites is necessary for proper GC migration in vivo. These findings identify a previously unknown role for VEGF in neuronal migration.
  Journal of Neuroscience 11/2010; 30(45):15052-66. · 7.11 Impact Factor