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  • 1.
    Bravi, Luca
    et al.
    IFOM, the FIRC Institute of Molecular Oncology Foundation.
    Malinverno, Matteo
    IFOM, the FIRC Institute of Molecular Oncology Foundation.
    Pisati, Federica
    Rudini, Noemi
    Cuttano, Roberto
    Pallini, Roberto
    Martini, Maurizio
    Larocca, Luigi Maria
    Locatelli, Marco
    Levi, Vincenzo
    Bertani, Giulio Andrea
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Lampugnani, Maria Grazia
    Endothelial Cells Lining Sporadic Cerebral Cavernous Malformation Cavernomas Undergo Endothelial-to-Mesenchymal Transition2016In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 47, no 3, p. 886-890Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND PURPOSE: Cerebral cavernous malformation (CCM) is characterized by multiple lumen vascular malformations in the central nervous system that can cause neurological symptoms and brain hemorrhages. About 20% of CCM patients have an inherited form of the disease with ubiquitous loss-of-function mutation in any one of 3 genes CCM1, CCM2, and CCM3. The rest of patients develop sporadic vascular lesions histologically similar to those of the inherited form and likely mediated by a biallelic acquired mutation of CCM genes in the brain vasculature. However, the molecular phenotypic features of endothelial cells in CCM lesions in sporadic patients are still poorly described. This information is crucial for a targeted therapy.

    METHODS: We used immunofluorescence microscopy and immunohistochemistry to analyze the expression of endothelial-to-mesenchymal transition markers in the cavernoma of sporadic CCM patients in parallel with human familial cavernoma as a reference control.

    RESULTS: We report here that endothelial cells, a cell type critically involved in CCM development, undergo endothelial-to-mesenchymal transition in the lesions of sporadic patients. This switch in endothelial phenotype has been described only in genetic CCM patients and in murine models of the disease. In addition, TGF-β/p-Smad- and β-catenin-dependent signaling pathways seem activated in sporadic cavernomas as in familial ones.

    CONCLUSIONS: Our findings support the use of common therapeutic strategies for both sporadic and genetic CCM malformations.

  • 2. Bravi, Luca
    et al.
    Rudini, Noemi
    Cuttano, Roberto
    Giampietro, Costanza
    Maddaluno, Luigi
    Ferrarini, Luca
    Adams, Ralf H.
    Corada, Monica
    Boulday, Gwenola
    Tournier-Lasserve, Elizabeth
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Lampugnani, Maria Grazia
    Sulindac metabolites decrease cerebrovascular malformations in CCM3-knockout mice2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 27, p. 8421-8426Article in journal (Refereed)
    Abstract [en]

    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.

  • 3.
    Castro, Marco
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Laviña, Bàrbara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Ando, Koji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Álvarez-Aznar, Alberto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Brakebusch, Cord
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. FOM, the FIRC Institute of Molecular Oncology, Milan, Italy.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. AstraZeneca/Karolinska Integrated Cardio Metabolic Centre (ICMC), Karolinska Institutet.
    Gängel, Konstantin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    CDC42 deletion elicits cerebral vascular malformations via increased MEKK3-dependent KLF4 expressionManuscript (preprint) (Other academic)
  • 4.
    Chiang, Ivy Kim-Ni
    et al.
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Fritzsche, Martin
    Univ Oxford, Ludwig Inst Canc Res, Nuffield Dept Clin Med, Oxford OX3 7DQ, England..
    Pichol-Thievend, Cathy
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Neal, Alice
    Univ Oxford, Ludwig Inst Canc Res, Nuffield Dept Clin Med, Oxford OX3 7DQ, England..
    Holmes, Kelly
    Univ Cambridge, Li Ka Shing Ctr, Canc Res UK, Robinson Way, Cambridge CB2 0RE, England..
    Lagendijk, Anne
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Overman, Jeroen
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    D'Angelo, Donatella
    Univ Milan, Dipartimento Biosci, Via Celoria 26, I-20133 Milan, Italy..
    Omini, Alice
    Univ Milan, Dipartimento Biosci, Via Celoria 26, I-20133 Milan, Italy..
    Hermkens, Dorien
    Univ Munster, D-48149 Munster, Germany.;Westfalische Wilhelms Univ Munster WWU, Inst Cardiovasc Organogenesis & Regenerat, Fac Med, Mendelstr 7, D-48149 Munster, Germany.;CiM Cluster Excellence, Munster, Germany..
    Lesieur, Emmanuelle
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Liu, Ke
    Univ Liverpool, Inst Aging & Chron Dis, Liverpool L69 3GA, Merseyside, England..
    Ratnayaka, Indrika
    Univ Oxford, Ludwig Inst Canc Res, Nuffield Dept Clin Med, Oxford OX3 7DQ, England..
    Corada, Monica
    FIRC Inst Mol Oncol, IFOM, I-1620139 Milan, Italy..
    Bou-Gharios, George
    Univ Liverpool, Inst Aging & Chron Dis, Liverpool L69 3GA, Merseyside, England..
    Carroll, Jason
    Univ Cambridge, Li Ka Shing Ctr, Canc Res UK, Robinson Way, Cambridge CB2 0RE, England..
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. FIRC Inst Mol Oncol, IFOM, I-1620139 Milan, Italy.
    Schulte-Merker, Stefan
    Univ Munster, D-48149 Munster, Germany.;Westfalische Wilhelms Univ Munster WWU, Inst Cardiovasc Organogenesis & Regenerat, Fac Med, Mendelstr 7, D-48149 Munster, Germany.;CiM Cluster Excellence, Munster, Germany..
    Hogan, Benjamin
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Beltrame, Monica
    Univ Milan, Dipartimento Biosci, Via Celoria 26, I-20133 Milan, Italy..
    De Val, Sarah
    Univ Oxford, Ludwig Inst Canc Res, Nuffield Dept Clin Med, Oxford OX3 7DQ, England..
    Francois, Mathias
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    SoxF factors induce Notch1 expression via direct transcriptional regulation during early arterial development2017In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 144, no 14, p. 2629-2639Article in journal (Refereed)
    Abstract [en]

    Arterial specification and differentiation are influenced by a number of regulatory pathways. While it is known that the Vegfa-Notch cascade plays a central role, the transcriptional hierarchy controlling arterial specification has not been fully delineated. To elucidate the direct transcriptional regulators of Notch receptor expression in arterial endothelial cells, we used histone signatures, DNaseI hypersensitivity and ChIP-seq data to identify enhancers for the human NOTCH1 and zebrafish notch1b genes. These enhancerswere able to direct arterial endothelial cell-restricted expression in transgenic models. Genetic disruption of SoxF binding sites established a clear requirement for members of this group of transcription factors (SOX7, SOX17 and SOX18) to drive the activity of these enhancers in vivo. Endogenous deletion of the notch1b enhancer led to a significant loss of arterial connections to the dorsal aorta in Notch pathway-deficient zebrafish. Loss of SoxF function revealed that these factors are necessary for NOTCH1 and notch1b enhancer activity and for correct endogenous transcription of these genes. These findings position SoxF transcription factors directly upstream of Notch receptor expression during the acquisition of arterial identity in vertebrates.

  • 5.
    Cunha, Sara I.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. FIRC Institute of Molecular Oncology, Milan, Italy (E.D., M.G.L.); Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy (M.G.L.).
    Magnusson, Peetra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. FIRC Institute of Molecular Oncology, Milan, Italy (E.D., M.G.L.); Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy (M.G.L.).
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. FIRC Inst Mol Oncol, Milan, Italy..
    Lampugnani, Maria Grazia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. FIRC Inst Mol Oncol, Milan, Italy.;Ist Ric Farmacol Mario Negri, Milan, Italy..
    Deregulated TGF-beta/BMP Signaling in Vascular Malformations2017In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 121, no 8, p. 981-999Article, review/survey (Refereed)
    Abstract [en]

    Correct organization of the vascular tree requires the balanced activities of several signaling pathways that regulate tubulogenesis and vascular branching, elongation, and pruning. When this balance is lost, the vessels can be malformed and fragile, and they can lose arteriovenous differentiation. In this review, we concentrate on the transforming growth factor (TGF)-beta/bone morphogenetic protein (BMP) pathway, which is one of the most important and complex signaling systems in vascular development. Inactivation of these pathways can lead to altered vascular organization in the embryo. In addition, many vascular malformations are related to deregulation of TGF-beta/BMP signaling. Here, we focus on two of the most studied vascular malformations that are induced by deregulation of TGF-beta/BMP signaling: hereditary hemorrhagic telangiectasia (HHT) and cerebral cavernous malformation (CCM). The first of these is related to loss-of-function mutation of the TGF-beta/BMP receptor complex and the second to increased signaling sensitivity to TGF-beta/BMP. In this review, we discuss the potential therapeutic targets against these vascular malformations identified so far, as well as their basis in general mechanisms of vascular development and stability.

  • 6.
    Cuttano, Roberto
    et al.
    IFOM, Milan, Italy..
    Rudini, Noemi
    IFOM, Milan, Italy..
    Bravi, Luca
    IFOM, Milan, Italy..
    Corada, Monica
    IFOM, Milan, Italy..
    Giampietro, Costanza
    IFOM, Milan, Italy.;Univ Milan, Dept Biosci, Milan, Italy..
    Papa, Eleanna
    IFOM, Milan, Italy..
    Morini, Marco Francesco
    IFOM, Milan, Italy..
    Maddaluno, Luigi
    IFOM, Milan, Italy..
    Baeyens, Nicolas
    Yale Cardiovasc Res Ctr, New Haven, CT USA..
    Adams, Ralf H.
    Univ Munster, Max Planck Inst Mol Biomed, Fac Med, Dept Tissue Morphogenesis, D-48149 Munster, Germany..
    Jain, Mukesh K.
    Case Cardiovasc Res Inst, Cleveland, OH USA.;Harrington Heart & Vasc Inst, Cleveland, OH USA.;Univ Hosp Case Med Ctr, Dept Med, Cleveland, OH USA.;Case Western Reserve Univ, Sch Med, Univ Hosp Case Med Ctr, Cleveland, OH USA..
    Owens, Gary K.
    Univ Virginia, Sch Med, Robert M Berne Cardiovasc Res Ctr, Charlottesville, VA 22908 USA..
    Schwartz, Martin
    Yale Cardiovasc Res Ctr, New Haven, CT USA..
    Lampugnani, Maria Grazia
    IFOM, Milan, Italy.;Mario Negri Inst Pharmacol Res, Milan, Italy..
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. IFOM, Milan, Italy.;Univ Milan, Dept Oncol & Oncohematol, Milan, Italy..
    KLF4 is a key determinant in the development and progression of cerebral cavernous malformations2016In: EMBO Molecular Medicine, ISSN 1757-4676, E-ISSN 1757-4684, Vol. 8, no 1, p. 6-24Article in journal (Refereed)
    Abstract [en]

    Cerebral cavernous malformations (CCMs) are vascular malformations located within the central nervous system often resulting in cerebral hemorrhage. Pharmacological treatment is needed, since current therapy is limited to neurosurgery. Familial CCM is caused by loss-of-function mutations in any of Ccm1, Ccm2, and Ccm3 genes. CCM cavernomas are lined by endothelial cells (ECs) undergoing endothelial-to-mesenchymal transition (EndMT). This switch in phenotype is due to the activation of the transforming growth factor beta/bone morphogenetic protein (TGFb/BMP) signaling. However, the mechanism linking Ccm gene inactivation and TGFb/ BMP-dependent EndMT remains undefined. Here, we report that Ccm1 ablation leads to the activation of a MEKK3-MEK5-ERK5MEF2 signaling axis that induces a strong increase in Kruppel-like factor 4 (KLF4) in ECs in vivo. KLF4 transcriptional activity is responsible for the EndMT occurring in CCM1-null ECs. KLF4 promotes TGFb/BMP signaling through the production of BMP6. Importantly, in endothelial-specific Ccm1 and Klf4 double knockout mice, we observe a strong reduction in the development of CCM and mouse mortality. Our data unveil KLF4 as a therapeutic target for CCM.

  • 7.
    Dejana, Elisabetta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. FIRC Inst Mol Oncol, Vasc Biol Unit, I-20129 Milan, Italy..
    Hirschi, Karen K.
    Yale Cardiovasc Res Ctr, Dept Internal Med, New Haven, CT 06511 USA.;Yale Cardiovasc Res Ctr, Dept Genet, New Haven, CT 06511 USA.;Yale Cardiovasc Res Ctr, Dept Biomed Engn, New Haven, CT 06511 USA..
    Simons, Michael
    Yale Univ, Sch Med, Yale Cardiovasc Res Ctr, Dept Internal Med, 333 Cedar St, New Haven, CT 06511 USA.;Yale Univ, Sch Med, Dept Cell Biol, 333 Cedar St, New Haven, CT 06511 USA..
    The molecular basis of endothelial cell plasticity2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 14361Article, review/survey (Refereed)
    Abstract [en]

    The endothelium is capable of remarkable plasticity. In the embryo, primitive endothelial cells differentiate to acquire arterial, venous or lymphatic fates. Certain endothelial cells also undergo hematopoietic transition giving rise to multi-lineage hematopoietic stem and progenitors while others acquire mesenchymal properties necessary for heart development. In the adult, maintenance of differentiated endothelial state is an active process requiring constant signalling input. The failure to do so leads to the development of endothelial-to-mesenchymal transition that plays an important role in pathogenesis of a number of diseases. A better understanding of these phenotypic changes may lead to development of new therapeutic interventions.

  • 8.
    Erba, Benedetta Gaia
    et al.
    FIRC Inst Mol Oncol IFOM Fdn, Vasc Biol Lab, Milan, Italy..
    Gruppi, Cristian
    Univ Pavia, Dept Mol Med, Pavia, Italy..
    Corada, Monica
    FIRC Inst Mol Oncol IFOM Fdn, Vasc Biol Lab, Milan, Italy..
    Pisati, Federica
    FIRC Inst Mol Oncol IFOM Fdn, Vasc Biol Lab, Milan, Italy.;Cogentech, Hystopatol Unit, Milan, Italy..
    Rosti, Vittorio
    Policlin San Matteo Fdn, Ctr Study & Treatment Myelofibrosis, Ctr Study Myelofibrosis, Biotechnol Res Labs,Ist Ricovero & Cura Carattere, Pavia, Italy..
    Bartalucci, Niccolo'
    Univ Florence, Sect Haematol, Dept Med & Surg Care, Florence, Italy..
    Villeval, Jean-Luc
    Inst Gustave Roussy, INSERM, U1009, Villejuif, France.;Univ Paris XI, Villejuif, France..
    Vannucchi, Alessandro Maria
    Univ Florence, Sect Haematol, Dept Med & Surg Care, Florence, Italy..
    Barosi, Giovanni
    Policlin San Matteo Fdn, Ctr Study & Treatment Myelofibrosis, Ctr Study Myelofibrosis, Biotechnol Res Labs,Ist Ricovero & Cura Carattere, Pavia, Italy..
    Balduini, Alessandra
    Univ Pavia, Dept Mol Med, Pavia, Italy..
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. FIRC Inst Mol Oncol IFOM Fdn, Vasc Biol Lab, Milan, Italy..
    Endothelial-to-Mesenchymal Transition in Bone Marrow and Spleen of Primary Myelofibrosis2017In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 187, no 8, p. 1879-1892Article in journal (Refereed)
    Abstract [en]

    Primary myelofibrosis is characterized by the development of fibrosis in the bone marrow that contributes to ineffective hematopoiesis. Bone marrow fibrosis is the result of a complex and not yet fully understood interaction among megakaryocytes, myeloid cells, fibroblasts, and endothelial cells. Here, we report that >30% of the endothelial cells in the small vessels of the bone marrow and spleen of patients with primary myelofibrosis have a mesenchymal phenotype, which is suggestive of the process known as endothelial-to-mesenchymal transition (EndMT). EndMT can be reproduced in vitro by incubation of cultured endothelial progenitor cells or spleen-derived endothelial cells with inflammatory cytokines. Megakaryocytes appear to be implicated in this process, because EndMT mainly occurs in the microvessels close to these cells, and because megakaryocyte-derived supernatant fluid can reproduce the EndMT switch in vitro. Furthermore, EndMT is an early event in a JAK2-V617F knock-in mouse model of primary myelofibrosis. Overall, these data show for the first time that microvascular endothelial cells in the bone marrow and spleen of patients with primary myelofibrosis show functional and morphologic changes that are associated to the mesenchymal phenotype.

  • 9.
    Giampietro, C.
    et al.
    FIRC Inst Mol Oncol, IFOM, Milan, Italy..
    Disanza, A.
    FIRC Inst Mol Oncol, IFOM, Milan, Italy..
    Scita, G.
    FIRC Inst Mol Oncol, IFOM, Milan, Italy..
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. FIRC Inst Mol Oncol, IFOM, Milan, Italy..
    VE-cadherin modulates YAP intracellular localization and signalling2016In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 283, p. 48-48Article in journal (Refereed)
  • 10.
    Giampietro, Costanza
    et al.
    FIRC Inst Mol Oncol, I-20139 Milan, Italy.;Univ Milan, Dept Biosci, I-20133 Milan, Italy..
    Deflorian, Gianluca
    FIRC Inst Mol Oncol, I-20139 Milan, Italy..
    Gallo, Stefania
    CNR, Ist Genet Mol, I-27100 Pavia, Italy.;IUSS Ist Univ Super, I-27100 Pavia, Italy..
    Di Matteo, Anna
    CNR, Ist Genet Mol, I-27100 Pavia, Italy.;Lazzaro Spallanzani Univ Pavia, Dipartimento Biol & Biotecnol, I-27100 Pavia, Italy..
    Pradella, Davide
    CNR, Ist Genet Mol, I-27100 Pavia, Italy.;Lazzaro Spallanzani Univ Pavia, Dipartimento Biol & Biotecnol, I-27100 Pavia, Italy..
    Bonomi, Serena
    CNR, Ist Genet Mol, I-27100 Pavia, Italy..
    Belloni, Elisa
    CNR, Ist Genet Mol, I-27100 Pavia, Italy..
    Nyqvist, Daniel
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, S-17177 Stockholm, Sweden..
    Quaranta, Valeria
    CNR, Ist Genet Mol, I-27100 Pavia, Italy..
    Confalonieri, Stefano
    FIRC Inst Mol Oncol, I-20139 Milan, Italy.;Ist Europeo Oncol, Dipartimento Oncol Sperimentale, I-20141 Milan, Italy..
    Bertalot, Giovanni
    Ist Europeo Oncol, Dipartimento Oncol Sperimentale, I-20141 Milan, Italy..
    Orsenigo, Fabrizio
    FIRC Inst Mol Oncol, I-20139 Milan, Italy..
    Pisati, Federica
    FIRC Inst Mol Oncol, I-20139 Milan, Italy..
    Ferrero, Elisabetta
    Ist Sci San Raffaele, Dept Oncol, I-20132 Milan, Italy..
    Biamonti, Giuseppe
    CNR, Ist Genet Mol, I-27100 Pavia, Italy..
    Fredrickx, Evelien
    Ist Sci San Raffaele, Div Neurosci, I-20132 Milan, Italy.;Ist Sci San Raffaele, INSPE, I-20132 Milan, Italy..
    Taveggia, Carla
    Ist Sci San Raffaele, Div Neurosci, I-20132 Milan, Italy.;Ist Sci San Raffaele, INSPE, I-20132 Milan, Italy..
    Wyatt, Chris D. R.
    Ctr Genom Regulat CRG, EMBL CRG Res Unit Syst Biol, Barcelona 08003, Spain.;Univ Pompeu Fabra UPF, Barcelona 08003, Spain..
    Irimia, Manuel
    Ctr Genom Regulat CRG, EMBL CRG Res Unit Syst Biol, Barcelona 08003, Spain.;Univ Pompeu Fabra UPF, Barcelona 08003, Spain..
    Di Fiore, Pier Paolo
    FIRC Inst Mol Oncol, I-20139 Milan, Italy.;Ist Europeo Oncol, Dipartimento Oncol Sperimentale, I-20141 Milan, Italy.;Univ Milan, Dipartimento Sci Salute, I-20122 Milan, Italy..
    Blencowe, Benjamin J.
    Univ Toronto, Donnelly Ctr Cellular & Biomol Res, Toronto, ON M5S 3E1, Canada..
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. FIRC Inst Mol Oncol, I-20139 Milan, Italy.;Univ Milan, Dept Biosci, I-20133 Milan, Italy..
    Ghigna, Claudia
    CNR, Ist Genet Mol, I-27100 Pavia, Italy..
    The alternative splicing factor Nova2 regulates vascular development and lumen formation2015In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, article id 8479Article in journal (Refereed)
    Abstract [en]

    Vascular lumen formation is a fundamental step during angiogenesis; yet, the molecular mechanisms underlying this process are poorly understood. Recent studies have shown that neural and vascular systems share common anatomical, functional and molecular similarities. Here we show that the organization of endothelial lumen is controlled at the post-transcriptional level by the alternative splicing (AS) regulator Nova2, which was previously considered to be neural cell-specific. Nova2 is expressed during angiogenesis and its depletion disrupts vascular lumen formation in vivo. Similarly, Nova2 depletion in cultured endothelial cells (ECs) impairs the apical distribution and the downstream signalling of the Par polarity complex, resulting in altered EC polarity, a process required for vascular lumen formation. These defects are linked to AS changes of Nova2 target exons affecting the Par complex and its regulators. Collectively, our results reveal that Nova2 functions as an AS regulator in angiogenesis and is a novel member of the 'angioneurins' family.

  • 11. Giampietro, Costanza
    et al.
    Disanza, Andrea
    Bravi, Luca
    Barrios-Rodiles, Miriam
    Corada, Monica
    Frittoli, Emanuela
    Savorani, Cecilia
    Lampugnani, Maria Grazia
    Boggetti, Barbara
    Niessen, Carien
    Wrana, Jeff L
    Scita, Giorgio
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    The actin-binding protein EPS8 binds VE-cadherin and modulates YAP localization and signaling2015In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 211, no 6, p. 1177-1192Article in journal (Refereed)
    Abstract [en]

    Vascular endothelial (VE)-cadherin transfers intracellular signals contributing to vascular hemostasis. Signaling through VE-cadherin requires association and activity of different intracellular partners. Yes-associated protein (YAP)/TAZ transcriptional cofactors are important regulators of cell growth and organ size. We show that EPS8, a signaling adapter regulating actin dynamics, is a novel partner of VE-cadherin and is able to modulate YAP activity. By biochemical and imaging approaches, we demonstrate that EPS8 associates with the VE-cadherin complex of remodeling junctions promoting YAP translocation to the nucleus and transcriptional activation. Conversely, in stabilized junctions, 14-3-3-YAP associates with the VE-cadherin complex, whereas Eps8 is excluded. Junctional association of YAP inhibits nuclear translocation and inactivates its transcriptional activity both in vitro and in vivo in Eps8-null mice. The absence of Eps8 also increases vascular permeability in vivo, but did not induce other major vascular defects. Collectively, we identified novel components of the adherens junction complex, and we introduce a novel molecular mechanism through which the VE-cadherin complex controls YAP transcriptional activity.

  • 12.
    Krispin, Shlomo
    et al.
    Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Dev Biol, NIH, Bethesda, MD 20892 USA..
    Stratman, Amber N.
    Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Dev Biol, NIH, Bethesda, MD 20892 USA..
    Melick, Chase H.
    Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Dev Biol, NIH, Bethesda, MD 20892 USA..
    Stan, Radu V.
    Dartmouth Coll, Geisel Sch Med, Dept Biochem & Cell Biol, 1 Med Ctr Dr, Lebanon, NH 03756 USA.;Dartmouth Coll, Geisel Sch Med, Dept Pathol, 1 Med Ctr Dr, Lebanon, NH 03756 USA..
    Malinverno, Matteo
    FIRC Inst Mol Oncol Fdn, Vasc Biol Program, IFOM, Milan, Italy..
    Gleklen, Jamie
    Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Dev Biol, NIH, Bethesda, MD 20892 USA..
    Castranova, Daniel
    Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Dev Biol, NIH, Bethesda, MD 20892 USA..
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. FIRC Inst Mol Oncol Fdn, Vasc Biol Program, IFOM, Milan, Italy.
    Weinstein, Brant M.
    Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Dev Biol, NIH, Bethesda, MD 20892 USA..
    Growth Differentiation Factor 6 Promotes Vascular Stability by Restraining Vascular Endothelial Growth Factor Signaling2018In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 38, no 2, p. 353-362Article in journal (Refereed)
    Abstract [en]

    Objective - The assembly of a functional vascular system requires a coordinated and dynamic transition from activation to maturation. High vascular endothelial growth factor activity promotes activation, including junction destabilization and cell motility. Maturation involves junctional stabilization and formation of a functional endothelial barrier. The identity and mechanism of action of prostabilization signals are still mostly unknown. Bone morphogenetic protein receptors and their ligands have important functions during embryonic vessel assembly and maturation. Previous work has suggested a role for growth differentiation factor 6 (GDF6; bone morphogenetic protein 13) in vascular integrity although GDF6's mechanism of action was not clear. Therefore, we sought to further explore the requirement for GDF6 in vascular stabilization.

    Approach and Results - We investigated the role of GDF6 in promoting endothelial vascular integrity in vivo in zebrafish and in cultured human umbilical vein endothelial cells in vitro. We report that GDF6 promotes vascular integrity by counteracting vascular endothelial growth factor activity. GDF6-deficient endothelium has increased vascular endothelial growth factor signaling, increased vascular endothelial-cadherin Y658 phosphorylation, vascular endothelial-cadherin delocalization from cell-cell interfaces, and weakened endothelial cell adherence junctions that become prone to vascular leak.

    Conclusions - Our results suggest that GDF6 promotes vascular stabilization by restraining vascular endothelial growth factor signaling. Understanding how GDF6 affects vascular integrity may help to provide insights into hemorrhage and associated vascular pathologies in humans.

  • 13.
    Krispin, Shlomo
    et al.
    Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Dev Biol, NIH, Bethesda, MD 20892 USA..
    Stratman, Amber N.
    Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Dev Biol, NIH, Bethesda, MD 20892 USA..
    Melick, Chase H.
    Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Dev Biol, NIH, Bethesda, MD 20892 USA..
    Stan, Radu V.
    Dartmouth Coll, Geisel Sch Med, Dept Biochem & Cell Biol, 1 Med Ctr Dr, Lebanon, NH 03756 USA.;Dartmouth Coll, Geisel Sch Med, Dept Pathol, 1 Med Ctr Dr, Lebanon, NH 03756 USA..
    Malinverno, Matteo
    FIRC Inst Mol Oncol Fdn, Vasc Biol Program, IFOM, Milan, Italy..
    Gleklen, Jamie
    Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Dev Biol, NIH, Bethesda, MD 20892 USA..
    Castranova, Daniel
    Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Dev Biol, NIH, Bethesda, MD 20892 USA..
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. FIRC Inst Mol Oncol Fdn, Vasc Biol Program, IFOM, Milan, Italy.
    Weinstein, Brant M.
    Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Dev Biol, NIH, Bethesda, MD 20892 USA..
    Growth Differentiation Factor 6 Promotes Vascular Stability by Restraining Vascular Endothelial Growth Factor Signaling2018In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 38, no 2, p. 353-362Article in journal (Refereed)
    Abstract [en]

    Objective

    The assembly of a functional vascular system requires a coordinated and dynamic transition from activation to maturation. High vascular endothelial growth factor activity promotes activation, including junction destabilization and cell motility. Maturation involves junctional stabilization and formation of a functional endothelial barrier. The identity and mechanism of action of prostabilization signals are still mostly unknown. Bone morphogenetic protein receptors and their ligands have important functions during embryonic vessel assembly and maturation. Previous work has suggested a role for growth differentiation factor 6 (GDF6; bone morphogenetic protein 13) in vascular integrity although GDF6's mechanism of action was not clear. Therefore, we sought to further explore the requirement for GDF6 in vascular stabilization.

    Approach and Results

    We investigated the role of GDF6 in promoting endothelial vascular integrity in vivo in zebrafish and in cultured human umbilical vein endothelial cells in vitro. We report that GDF6 promotes vascular integrity by counteracting vascular endothelial growth factor activity. GDF6-deficient endothelium has increased vascular endothelial growth factor signaling, increased vascular endothelial-cadherin Y658 phosphorylation, vascular endothelial-cadherin delocalization from cell-cell interfaces, and weakened endothelial cell adherence junctions that become prone to vascular leak.

    Conclusions

    Our results suggest that GDF6 promotes vascular stabilization by restraining vascular endothelial growth factor signaling. Understanding how GDF6 affects vascular integrity may help to provide insights into hemorrhage and associated vascular pathologies in humans.

  • 14.
    Lampugnani, Maria Grazia
    et al.
    Inst Mol Oncol Fdn, FIRC.;Mario Negri Inst Pharmacol Res..
    Malinverno, Matteo
    Inst Mol Oncol Fdn, FIRC..
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Inst Mol Oncol Fdn, FIRC.;Milano Univ, Sch Sci, Dept Biosci.;Milano Univ, Sch Med, Dept Oncol..
    Rudini, Noemi
    Inst Mol Oncol Fdn, FIRC..
    Endothelial cell disease: emerging knowledge from cerebral cavernous malformations2017In: Current opinion in hematology, ISSN 1065-6251, E-ISSN 1531-7048, Vol. 24, no 3, p. 256-264Article, review/survey (Refereed)
    Abstract [en]

    Purpose of review Endothelial cells dysfunctions are crucial determinants of several human diseases. We review here the most recent reports on endothelial cell defects in cerebral cavernous malformations (CCMs), particularly focusing on adherens junctions. CCM is a vascular disease that affects specifically the venous microvessels of the central nervous system and which is caused by loss-of-function mutation in any one of the three CCM genes (CCM1, 2 or 3) in endothelial cells. The phenotypic result of these mutations are focal vascular malformations that are permeable and fragile causing neurological symptoms and occasionally haemorrhagic stroke. Recent findings CCM is still an incurable disease, as no pharmacological treatment is available, besides surgery. The definition of the molecular alterations ensuing loss of function mutation of CCM genes is contributing to orientate the testing of targeted pharmacological tools Several signalling pathways are altered in the three genotypes in a similar way and concur in the acquisition of mesenchymal markers in endothelial cells. However, also genotype-specific defects are reported, in particular for the CCM1 and CCM3 mutation. Summary Besides the specific CCM disease, the characterization of endothelial alterations in CCM has the potentiality to shed light on basic molecular regulations as the acquisition and maintenance of organ and vascular site specificity of endothelial cells.

  • 15.
    Li, Xiujuan
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Padhan, Narendra
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala Univ, Sci Life Lab, Rudbeck Lab, Dept Immunol Genet & Pathol, S-75185 Uppsala, Sweden..
    Sjöström, Elisabet O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala Univ, Sci Life Lab, Rudbeck Lab, Dept Immunol Genet & Pathol, S-75185 Uppsala, Sweden..
    Roche, Francis P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Testini, Chiara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Honkura, Naoki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sainz-Jaspeado, Miguel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gordon, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bentley, Katie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, 330 Brookline Ave, Boston, MA 02215 USA..
    Philippides, Andrew
    Univ Sussex, Ctr Computat Neurosci & Robot, Chichester 1 CI 104, Brighton BN1 9RH, E Sussex, England..
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. IFOM IEO Campus, Via Adamello 16, I-20139 Milan, Italy..
    Stan, Radu V.
    Dartmouth Coll, Dept Pathol, Geisel Sch Med Dartmouth, Lebanon, NH 03756 USA..
    Vestweber, Dietmar
    Max Planck Inst Mol Biomed, Dept Vasc Cell Biol, Rontgenstr 20, D-48149 Munster, Germany..
    Ballmer-Hofer, Kurt
    Paul Scherrer Inst, Biomol Res, Mol Cell Biol, CH-5232 Villigen, Switzerland..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, S-17177 Stockholm, Sweden..
    Pietras, Kristian
    Lund Univ, Medicon Village, Translat Canc Res, Bldg 404-A3, S-22381 Lund, Sweden..
    Jansson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 11017Article in journal (Refereed)
    Abstract [en]

    The specific role of VEGFA-induced permeability and vascular leakage in physiology and pathology has remained unclear. Here we show that VEGFA-induced vascular leakage depends on signalling initiated via the VEGFR2 phosphosite Y949, regulating dynamic c-Src and VE-cadherin phosphorylation. Abolished Y949 signalling in the mouse mutant Vegfr2(Y949F/Y949F) leads to VEGFA-resistant endothelial adherens junctions and a block in molecular extravasation. Vessels in Vegfr2(Y949F/Y949F) mice remain sensitive to inflammatory cytokines, and vascular morphology, blood pressure and flow parameters are normal. Tumour-bearing Vegfr2(Y949F/Y949F) mice display reduced vascular leakage and oedema, improved response to chemotherapy and, importantly, reduced metastatic spread. The inflammatory infiltration in the tumour micro-environment is unaffected. Blocking VEGFA-induced disassembly of endothelial junctions, thereby suppressing tumour oedema and metastatic spread, may be preferable to full vascular suppression in the treatment of certain cancer forms.

  • 16. Lugano, Roberta
    et al.
    Vemuri, Kalyani
    Yu, Di
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Essand, Magnus
    Johansson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    CD93 promotes integrin-β1 activation and fibronectin fibrillogenesis during tumor angiogenesis.2018In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, article id 97459Article in journal (Refereed)
    Abstract [en]

    Tumor angiogenesis occurs through regulation of genes that orchestrate endothelial sprouting and vessel maturation, including deposition of a vessel-associated extracellular matrix. CD93 is a transmembrane receptor that is up-regulated in tumor vessels in many cancers, including high-grade glioma. Here, we demonstrate that CD93 regulates integrin-β1-signaling and organization of fibronectin fibrillogenesis during tumor vascularization. In endothelial cells and mouse retina, CD93 was found to be expressed in endothelial filopodia and to promote filopodia formation. The CD93 localization to endothelial filopodia was stabilized by interaction with multimerin-2 (MMRN2), which inhibited its proteolytical cleavage. The CD93-MMRN2 complex was required for activation of integrin-β1, phosphorylation of focal adhesion kinase (FAK) and fibronectin fibrillogenesis in endothelial cells. Consequently, tumor vessels in gliomas implanted orthotopically in CD93-deficient mice showed diminished activation of integrin-β1 and lacked organization of fibronectin into fibrillar structures. These findings demonstrate a key role of CD93 in vascular maturation and organization of the extracellular matrix in tumors, identifying it as a potential target for therapy.

  • 17.
    Malinverno, Matteo
    et al.
    FIRC Inst Mol Oncol IFOM Fdn, Milan, Italy..
    Corada, Monica
    FIRC Inst Mol Oncol IFOM Fdn, Milan, Italy..
    Ferrarini, Luca
    FIRC Inst Mol Oncol IFOM Fdn, Milan, Italy..
    Formicola, Luigi
    Sorbonne Univ, Univ Pierre & Marie Curie, Stem Cells & Regenerat Med, Inst Cardiometab & Nutr ICAN UMRS 1166, Paris, France.;INSERM, Paris, France..
    Marazzi, Giovanna
    Sorbonne Univ, Univ Pierre & Marie Curie, Stem Cells & Regenerat Med, Inst Cardiometab & Nutr ICAN UMRS 1166, Paris, France.;INSERM, Paris, France..
    Sassoon, David
    Sorbonne Univ, Univ Pierre & Marie Curie, Stem Cells & Regenerat Med, Inst Cardiometab & Nutr ICAN UMRS 1166, Paris, France.;INSERM, Paris, France..
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. FIRC Inst Mol Oncol IFOM Fdn, Milan, Italy.;Milan Univ, Sch Sci, Dept Biosci, Milan, Italy.;Milan Univ, Sch Med, Dept Oncol, Milan, Italy..
    Peg3/PW1 Is a Marker of a Subset of Vessel Associated Endothelial Progenitors2017In: Stem Cells, ISSN 1066-5099, E-ISSN 1549-4918, Vol. 35, no 5, p. 1328-1340Article in journal (Refereed)
    Abstract [en]

    Vascular associated endothelial cell (ECs) progenitors are still poorly studied and their role in the newly forming vasculature at embryonic or postnatal stage remains elusive. In the present work, we first defined a set of genes highly expressed during embryo development and strongly downregulated in the adult mouse. In this group, we then concentrated on the progenitor cell marker Peg3/PW1. By in vivo staining of the vasculature we found that only a subset of cells coexpressed endothelial markers and PW1. These cells were quite abundant in the embryo vasculature but declined in number at postnatal and adult stages. Using a reporter mouse for PW1 expression, we have been able to isolate PW1-positive (PW1posECs) and negative endothelial cells (PW1negECs). PW1-positive cells were highly proliferative in comparison to PW1negECs and were able to form colonies when seeded at clonal dilution. Furthermore, by RNAseq analysis, PW1posECs expressed endothelial cell markers together with mesenchymal and stem cell markers. When challenged by endothelial growth factors in vitro, PW1posECs were able to proliferate more than PW1negECs and to efficiently form new vessels in vivo. Taken together these data identify a subset of vessel associated endothelial cells with characteristics of progenitor cells. Considering their high proliferative potential these cells may be of particular importance to design therapies to improve the perfusion of ischemic tissues or to promote vascular repair.

  • 18.
    Morini, Marco F.
    et al.
    FIRC Inst Mol Oncol, IFOM, Via Adamello 16, I-20139 Milan, Italy.;Univ Basel, Dept Biomed, Basel, Switzerland..
    Giampietro, Costanza
    FIRC Inst Mol Oncol, IFOM, Via Adamello 16, I-20139 Milan, Italy.;Swiss Fed Inst Technol, Dept Mech & Proc Engn, Lab Thermodynam Emerging Technol, Zurich, Switzerland..
    Corada, Monica
    FIRC Inst Mol Oncol, IFOM, Via Adamello 16, I-20139 Milan, Italy..
    Pisati, Federica
    FIRC Inst Mol Oncol, IFOM, Via Adamello 16, I-20139 Milan, Italy.;Cogentech, Milan, Italy..
    Lavarone, Elisa
    European Inst Oncol, Dept Expt Oncol, Milan, Italy..
    Cunha, Sara I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Conze, Lei Liu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    O'Reilly, Nicola
    Francis Crick Inst, Peptide Chem, London, England..
    Joshi, Dhira
    Francis Crick Inst, Peptide Chem, London, England..
    Kjaer, Svend
    Francis Crick Inst, Struct Biol, London, England..
    George, Roger
    Francis Crick Inst, Struct Biol, London, England..
    Nye, Emma
    Francis Crick Inst, Expt Histopathol, London, England..
    Ma, Anqi
    Icahn Sch Med Mt Sinai, Ctr Chem Biol & Drug Discovery, Tisch Canc Inst, Dept Pharmacol Sci, New York, NY USA.;Icahn Sch Med Mt Sinai, Ctr Chem Biol & Drug Discovery, Tisch Canc Inst, Dept Oncol Sci, New York, NY USA..
    Jin, Jian
    Icahn Sch Med Mt Sinai, Ctr Chem Biol & Drug Discovery, Tisch Canc Inst, Dept Pharmacol Sci, New York, NY USA.;Icahn Sch Med Mt Sinai, Ctr Chem Biol & Drug Discovery, Tisch Canc Inst, Dept Oncol Sci, New York, NY USA..
    Mitter, Richard
    Francis Crick Inst, Bioinformat & Biostat Dept, London, England..
    Lupia, Michela
    European Inst Oncol, Unit Gynecol Oncol Res, Milan, Italy..
    Cavallaro, Ugo
    European Inst Oncol, Unit Gynecol Oncol Res, Milan, Italy..
    Pasini, Diego
    European Inst Oncol, Dept Expt Oncol, Milan, Italy..
    Calado, Dinis P.
    Francis Crick Inst, Immun & Canc Lab, 1 Midland Rd, London NW1 1AT, England..
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. FIRC Inst Mol Oncol, IFOM, Via Adamello 16, I-20139 Milan, Italy.;Univ Milan, Dept Oncol & Hematooncol, Milan, Italy..
    Taddei, Andrea
    FIRC Inst Mol Oncol, IFOM, Via Adamello 16, I-20139 Milan, Italy.;Francis Crick Inst, Immun & Canc Lab, 1 Midland Rd, London NW1 1AT, England..
    VE-Cadherin-Mediated Epigenetic Regulation of Endothelial Gene Expression2018In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 122, no 2, p. 231-245Article in journal (Refereed)
    Abstract [en]

    Rationale: The mechanistic foundation of vascular maturation is still largely unknown. Several human pathologies are characterized by deregulated angiogenesis and unstable blood vessels. Solid tumors, for instance, get their nourishment from newly formed structurally abnormal vessels which present wide and irregular interendothelial junctions. Expression and clustering of the main endothelial-specific adherens junction protein, VEC (vascular endothelial cadherin), upregulate genes with key roles in endothelial differentiation and stability.

    Objective: We aim at understanding the molecular mechanisms through which VEC triggers the expression of a set of genes involved in endothelial differentiation and vascular stabilization.

    Methods and Results: We compared a VEC-null cell line with the same line reconstituted with VEC wild-type cDNA. VEC expression and clustering upregulated endothelial-specific genes with key roles in vascular stabilization including claudin-5, vascular endothelial-protein tyrosine phosphatase (VE-PTP), and von Willebrand factor (vWf). Mechanistically, VEC exerts this effect by inhibiting polycomb protein activity on the specific gene promoters. This is achieved by preventing nuclear translocation of FoxO1 (Forkhead box protein O1) and beta-catenin, which contribute to PRC2 (polycomb repressive complex-2) binding to promoter regions of claudin-5, VE-PTP, and vWf. VEC/beta-catenin complex also sequesters a core subunit of PRC2 (Ezh2 [enhancer of zeste homolog 2]) at the cell membrane, preventing its nuclear translocation. Inhibition of Ezh2/VEC association increases Ezh2 recruitment to claudin-5, VE-PTP, and vWf promoters, causing gene downregulation. RNA sequencing comparison of VEC-null and VEC-positive cells suggested a more general role of VEC in activating endothelial genes and triggering a vascular stability-related gene expression program. In pathological angiogenesis of human ovarian carcinomas, reduced VEC expression paralleled decreased levels of claudin-5 and VE-PTP.

    Conclusions: These data extend the knowledge of polycomb-mediated regulation of gene expression to endothelial cell differentiation and vessel maturation. The identified mechanism opens novel therapeutic opportunities to modulate endothelial gene expression and induce vascular normalization through pharmacological inhibition of the polycomb-mediated repression system.

  • 19.
    Spadoni, Ilaria
    et al.
    European Inst Oncol, Dept Expt Oncol, Milan, Italy..
    Zagato, Elena
    European Inst Oncol, Dept Expt Oncol, Milan, Italy..
    Bertocchi, Alice
    European Inst Oncol, Dept Expt Oncol, Milan, Italy..
    Paolinelli, Roberta
    Italian Fdn Canc Res FIRC, Inst Mol Oncol IFOM, Milan, Italy..
    Hot, Edina
    European Inst Oncol, Dept Expt Oncol, Milan, Italy..
    Di Sabatino, Antonio
    Univ Pavia, St Matteo Hosp, Dept Med 1, I-27100 Pavia, Italy..
    Caprioli, Flavio
    Osped Maggiore Policlin Milano, Fdn IRCCS Ca Granda, Unita Operat Gastroenterol & Endoscopia, Milan, Italy.;Univ Milan, Dipartimento Fisiopatol Med Chirurg & Trapianti, Milan, Italy..
    Bottiglieri, Luca
    European Inst Oncol, Dept Pathol & Lab Med, Milan, Italy..
    Oldani, Amanda
    Italian Fdn Canc Res FIRC, Inst Mol Oncol IFOM, Milan, Italy..
    Viale, Giuseppe
    European Inst Oncol, Dept Pathol & Lab Med, Milan, Italy..
    Penna, Giuseppe
    European Inst Oncol, Dept Expt Oncol, Milan, Italy..
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Italian Fdn Canc Res FIRC, Inst Mol Oncol IFOM, Milan, Italy.;Univ Milan, Dept Biosci, I-20122 Milan, Italy..
    Rescigno, Maria
    European Inst Oncol, Dept Expt Oncol, Milan, Italy.;Univ Milan, Dept Biosci, I-20122 Milan, Italy..
    A gut-vascular barrier controls the systemic dissemination of bacteria2015In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 350, no 6262, p. 830-834Article in journal (Refereed)
    Abstract [en]

    In healthy individuals, the intestinal microbiota cannot access the liver, spleen, or other peripheral tissues. Some pathogenic bacteria can reach these sites, however, and can induce a systemic immune response. How such compartmentalization is achieved is unknown. We identify a gut-vascular barrier (GVB) in mice and humans that controls the translocation of antigens into the bloodstream and prohibits entry of the microbiota. Salmonella typhimurium can penetrate the GVB in a manner dependent on its pathogenicity island (Spi) 2-encoded type III secretion system and on decreased beta-catenin-dependent signaling in gut endothelial cells. The GVB is modified in celiac disease patients with elevated serum transaminases, which indicates that GVB dismantling may be responsible for liver damage in these patients. Understanding the GVB may provide new insights into the regulation of the gut-liver axis.

1 - 19 of 19
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