Angiopoietin-1 mediates the proangiogenic activity of the bone morphogenic protein antagonist Drm

Mitola, Stefania; Moroni, Emanuela; Ravelli, Cosetta; Andrés, Germán; Belleri, Mirella; Presta, Marco

doi:10.1182/blood-2007-09-111450

Cited by 32 publications

(36 citation statements)

References 19 publications

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“…49 Previous observations had shown the ability of gremlin to induce NF-κB activation in ECs, leading to Ang-1 upregulation. 50 Here, we demonstrate the role of CREB in the modulation of ICAM-1 and VCAM-1 expression in gremlin-activated ECs and its involvement in monocyte/macrophage transendothelial migration. Of note, EC treatment with the cAMP analogous dibutyryl-cAMP fails to recapitulate the proinflammatory response elicited by gremlin ( Figure X in the onlineonly Data Supplement).…”

Section: Discussionmentioning

confidence: 55%

“…28 Also, gremlin stimulates EC intracellular signaling and motility in a BMP-independent manner, leading to a potent angiogenic response in vivo. 27,29 This is because of the capacity of gremlin to bind and activate VEGF receptor-2 (VEGFR2), the main transducer of VEGF-mediated angiogenic signals. 30,31 Also, gremlin interacts with heparan-sulfate proteoglycans that act as functional gremlin coreceptors in ECs, affecting its productive interaction with VEGFR2.…”

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confidence: 99%

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Cyclic Adenosine Monophosphate-Response Element–Binding Protein Mediates the Proangiogenic or Proinflammatory Activity of Gremlin

Corsini

Moroni

Ravelli

et al. 2014

ATVB

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Objective-Angiogenesis 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 Results-Gremlin 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. Corsini et al CREB in Gremlin Activity 137diseases 24 and cancer. [25][26][27] Gremlin acts as a bone morphogenic protein (BMP) antagonist by binding BMP2, BMP4, and BMP7. 28 Also, gremlin stimulates EC intracellular signaling and motility in a BMP-independent manner, leading to a potent angiogenic response in vivo. 27,29 This is because of the capacity of gremlin to bind and activate VEGF receptor-2 (VEGFR2), the main transducer of VEGF-mediated angiogenic signals. 30,31 Also, gremlin interacts with heparan-sulfate proteoglycans that act as functional gremlin coreceptors in ECs, affecting its productive interaction with VEGFR2.32 However, at variance with heparin-binding VEGFs, gremlin does not interact with the coreceptor neuropilin-1. 32 Thus, gremlin is a novel proangiogenic VEGFR2 agonist distinct from canonical VEGFs.Here, we demonstrate that gremlin induces a proinflammatory response in ECs by inducing the expression of various chemokines and cell adhesion molecules, causing a VEGFR2-mediated activation of CREB. In turn, CREB activation mediates the early phases of the angiogenic response to gremlin, including stimulation of EC motility and permeability, and leads to leukocyte-adhesion to ECs and their extravasation. In keeping with these observations, gremlin and gremlin-expressing tumor cells induce a proinflammatory or proangiogenic response in vivo that is suppressed by the anti-inflammatory drug hydrocortisone. These data point to a nonredundant role of CRE...

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Section: Discussionmentioning

confidence: 55%

mentioning

confidence: 99%

Cyclic Adenosine Monophosphate-Response Element–Binding Protein Mediates the Proangiogenic or Proinflammatory Activity of Gremlin

Corsini

Moroni

Ravelli

et al. 2014

ATVB

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“…Formation of radially growing cell sprouts was observed during the next 48 hours. 3 Sprouts were photographed at 40ϫ magnification with an IX51 inverted microscope equipped with a 4ϫ/0.10 numerical aperture objective and a Camedia C-4040 digital camera (Olympus). Data are expressed as total number of sprouts measured in 50 spheroids.…”

Section: Resultsmentioning

confidence: 99%

“…3 When indicated, ECs were stably transfected with a pcDNA3.1 expression vector harboring the mouse VEGFR2 complementary DNA.…”

Section: In Vitro Angiogenic Assaysmentioning

confidence: 99%

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Gremlin is a novel agonist of the major proangiogenic receptor VEGFR2

Mitola

Ravelli

Moroni

et al. 2010

Blood

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164

191

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The bone morphogenic protein antagonist gremlin is expressed during embryonic development and under different pathologic conditions, including cancer. Gremlin is a proangiogenic protein belonging to the cystine-knot superfamily that includes transforming growth factor-␤ proteins and the angiogenic vascu- IntroductionThe bone morphogenic protein (BMP) antagonist gremlin 1 induces angiogenesis in a BMP-independent manner by binding to as-yetunidentified endothelial cell (EC) membrane receptors and activating multiple tyrosine kinase-dependent intracellular signaling pathways in ECs. 2,3 Gremlin is produced by human tumors 4,5 and is expressed by fibroblast growth factor-2 (FGF2)-activated ECs and tumor endothelium. 2 Thus, gremlin may play paracrine/autocrine roles in tumor neovascularization. The identification of the EC receptors activated by gremlin has so far been unsuccessful.Vascular endothelial growth factor receptor-2 (VEGFR2) is the major proangiogenic tyrosine kinase receptor expressed by ECs and is activated by different members of the vascular endothelial growth factor (VEGF) family. 6 Both gremlin and VEGFs belong to the cystine-knot protein superfamily, 7 suggesting possible structural and/or functional similarities among these proangiogenic factors. On this basis, we investigated the capacity of gremlin to interact with and activate VEGFR2. The results demonstrate that gremlin binds and activates VEGFR2, leading to VEGFR2-dependent angiogenic responses in vitro and in vivo. Methods Ligand-receptor interaction assaysInteraction of VEGF-A and gremlin (R&D Systems) with the immobilized extracellular domain of VEGFR2 (sVEGFR2; Calbiochem) was analyzed by surface plasmon resonance (BIAcore Inc) and by competitive enzymelinked immunosorbent assay (ELISA). VEGFR2 interaction on the EC surface was characterized by cross-linking experiments, whereas VEGFR2 dimerization was assessed by fluorescence resonance energy transfer analysis. In vitro angiogenic assaysMotility and 3-dimensional gel invasion assays were performed on human, murine, and bovine ECs. 3 When indicated, ECs were stably transfected with a pcDNA3.1 expression vector harboring the mouse VEGFR2 complementary DNA.

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BMP growth factor signaling in a biomechanical context

et al. 2013

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Bone Morphogenetic Proteins (BMPs) are members of the transforming growth factor-β superfamily of secreted polypeptide growth factors and are important regulators in a multitude of cellular processes. To ensure the precise and balanced propagation of their pleiotropic signaling responses, BMPs and their corresponding signaling pathways are subject to tight control. A large variety of regulatory mechanisms throughout different biological levels combines into a complex network and provides the basis for physiological BMP function. This regulatory network not only includes biochemical factors but also mechanical cues. Both BMP signaling and mechanotransduction pathways are tightly interconnected and represent an elaborate signaling network active during development but also during organ homeostasis. Moreover, its dysregulation is associated with a number of human pathologies. A more detailed understanding of this crosstalk in respect to molecular interactions will be indispensable in the future, in particular to understand BMP-related diseases as well as with regard to an efficient clinical application of BMP ligands.

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Angiopoietin-1 mediates the proangiogenic activity of the bone morphogenic protein antagonist Drm

Cited by 32 publications

References 19 publications

Cyclic Adenosine Monophosphate-Response Element–Binding Protein Mediates the Proangiogenic or Proinflammatory Activity of Gremlin

Cyclic Adenosine Monophosphate-Response Element–Binding Protein Mediates the Proangiogenic or Proinflammatory Activity of Gremlin

Gremlin is a novel agonist of the major proangiogenic receptor VEGFR2

BMP growth factor signaling in a biomechanical context

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