• Michela Corsini, Emanuela Moroni, Cosetta Ravelli, Germán Andrés, Elisabetta Grillo, Imran H Ali, Derek P Brazil, Marco Presta, and Stefania Mitola.
• From the Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (M.C., E.M., C.R., E.G., M.P., S.M.); Electron Microscopy Unit, Centro de Biologia Molecular Severo Ochoa, Campus Cantoblanco, Madrid, Spain (G.A.); and Centre for Experimental Medicine, Queen's University Belfast, ICS-A, Grosvenor Road, Belfast BT12 6BA, UK (I.H.A., D.P.B.).
• Arterioscler. Thromb. Vasc. Biol. 2014 Jan 1; 34 (1): 136-45.

ObjectiveAngiogenesis and inflammation are closely related processes. Gremlin is a novel noncanonical vascular endothelial growth factor receptor-2 (VEGFR2) ligand that induces a proangiogenic response in endothelial cells (ECs). Here, we investigated the role of the cyclic adenosine monophosphate-response element (CRE)-binding protein (CREB) in mediating the proinflammatory and proangiogenic responses of ECs to gremlin.Approach And ResultsGremlin induces a proinflammatory response in ECs, leading to reactive oxygen species and cyclic adenosine monophosphate production and the upregulation of proinflammatory molecules involved in leukocyte extravasation, including chemokine (C-C motif) ligand-2 (Ccl2) and Ccl7, chemokine (C-X-C motif) ligand-1 (Cxcl1), vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1). Accordingly, gremlin induces the VEGFR2-dependent phosphorylation, nuclear translocation, and transactivating activity of CREB in ECs. CREB activation mediates the early phases of the angiogenic response to gremlin, including stimulation of EC motility and permeability, and leads to monocyte/macrophage adhesion to ECs and their extravasation. All these effects are inhibited by EC transfection with a dominant-negative CREB mutant or with a CREB-binding protein-CREB interaction inhibitor that competes for CREB/CRE binding. Also, both recombinant gremlin and gremlin-expressing tumor cells induce proinflammatory/proangiogenic responses in vivo that are suppressed by the anti-inflammatory drug hydrocortisone. Similar effects were induced by the canonical VEGFR2 ligand VEGF-A165.ConclusionsTogether, the results underline the tight cross-talk between angiogenesis and inflammation and demonstrate a crucial role of CREB activation in the modulation of the VEGFR2-mediated proinflammatory/proangiogenic response of ECs to gremlin.

65 keywords...

hide…