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  • Morini, Marco F.FIRC Inst Mol Oncol, IFOM, Via Adamello 16, I-20139 Milan, Italy.;Univ Basel, Dept Biomed, Basel, Switzerland. (author)

VE-Cadherin-Mediated Epigenetic Regulation of Endothelial Gene Expression

  • Article/chapterEnglish2018

Publisher, publication year, extent ...

  • LIPPINCOTT WILLIAMS & WILKINS,2018
  • electronicrdacarrier

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  • LIBRIS-ID:oai:DiVA.org:uu-349850
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-349850URI
  • https://doi.org/10.1161/CIRCRESAHA.117.312392DOI

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  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

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  • 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.

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  • Giampietro, CostanzaFIRC 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. (author)
  • Corada, MonicaFIRC Inst Mol Oncol, IFOM, Via Adamello 16, I-20139 Milan, Italy. (author)
  • Pisati, FedericaFIRC Inst Mol Oncol, IFOM, Via Adamello 16, I-20139 Milan, Italy.;Cogentech, Milan, Italy. (author)
  • Lavarone, ElisaEuropean Inst Oncol, Dept Expt Oncol, Milan, Italy. (author)
  • Cunha, Sara I.Uppsala universitet,Vaskulärbiologi(Swepub:uu)sarcu762 (author)
  • Conze, Lei LiuUppsala universitet,Vaskulärbiologi(Swepub:uu)leliu102 (author)
  • O'Reilly, NicolaFrancis Crick Inst, Peptide Chem, London, England. (author)
  • Joshi, DhiraFrancis Crick Inst, Peptide Chem, London, England. (author)
  • Kjaer, SvendFrancis Crick Inst, Struct Biol, London, England. (author)
  • George, RogerFrancis Crick Inst, Struct Biol, London, England. (author)
  • Nye, EmmaFrancis Crick Inst, Expt Histopathol, London, England. (author)
  • Ma, AnqiIcahn 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. (author)
  • Jin, JianIcahn 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. (author)
  • Mitter, RichardFrancis Crick Inst, Bioinformat & Biostat Dept, London, England. (author)
  • Lupia, MichelaEuropean Inst Oncol, Unit Gynecol Oncol Res, Milan, Italy. (author)
  • Cavallaro, UgoEuropean Inst Oncol, Unit Gynecol Oncol Res, Milan, Italy. (author)
  • Pasini, DiegoEuropean Inst Oncol, Dept Expt Oncol, Milan, Italy. (author)
  • Calado, Dinis P.Francis Crick Inst, Immun & Canc Lab, 1 Midland Rd, London NW1 1AT, England. (author)
  • Dejana, ElisabettaUppsala universitet,Vaskulärbiologi,FIRC Inst Mol Oncol, IFOM, Via Adamello 16, I-20139 Milan, Italy.;Univ Milan, Dept Oncol & Hematooncol, Milan, Italy.(Swepub:uu)elide443 (author)
  • Taddei, AndreaFIRC Inst Mol Oncol, IFOM, Via Adamello 16, I-20139 Milan, Italy.;Francis Crick Inst, Immun & Canc Lab, 1 Midland Rd, London NW1 1AT, England. (author)
  • FIRC Inst Mol Oncol, IFOM, Via Adamello 16, I-20139 Milan, Italy.;Univ Basel, Dept Biomed, Basel, Switzerland.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. (creator_code:org_t)

Related titles

  • In:Circulation Research: LIPPINCOTT WILLIAMS & WILKINS122:2, s. 231-2450009-73301524-4571

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