VE-cadherin-mediated epigenetic regulation of endothelial gene expression

Marco F. Morini, Costanza Giampietro, Monica Corada, Federica Pisati, Elisa Lavarone, Sara I. Cunha, Lei L. Conze, Nicola O'Reilly, Dhira Joshi, Svend Kjaer, Roger George, Emma Nye, Anqi Ma, Jian Jin, Richard Mitter, Michela Lupia, Ugo Cavallaro, Diego Pasini, Dinis P. Calado, Elisabetta DejanaAndrea Taddei

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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 β-catenin, which contribute to PRC2 (polycomb repressive complex-2) binding to promoter regions of claudin-5, VE-PTP, and vWf. VEC/β-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 VECnull 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.

Original languageEnglish
Pages (from-to)231-245
Number of pages15
JournalCirculation Research
Volume122
Issue number2
DOIs
Publication statusPublished - Jan 1 2018

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Gene Expression Regulation
Epigenomics
Class 3 Receptor-Like Protein Tyrosine Phosphatases
Claudin-5
Blood Vessels
von Willebrand Factor
Polycomb Repressive Complex 2
Genes
Catenins
Cluster Analysis
cadherin 5
Pathologic Neovascularization
RNA Sequence Analysis
Gene Expression
Adherens Junctions
Null Lymphocytes
Genetic Promoter Regions
Cell Differentiation
Proteins
Up-Regulation

Keywords

  • Blood vessels
  • Cadherin
  • Cell differentiation
  • Endothelial cells
  • Polycomb-group proteins

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Morini, M. F., Giampietro, C., Corada, M., Pisati, F., Lavarone, E., Cunha, S. I., ... Taddei, A. (2018). VE-cadherin-mediated epigenetic regulation of endothelial gene expression. Circulation Research, 122(2), 231-245. https://doi.org/10.1161/CIRCRESAHA.117.312392

VE-cadherin-mediated epigenetic regulation of endothelial gene expression. / Morini, Marco F.; Giampietro, Costanza; Corada, Monica; Pisati, Federica; Lavarone, Elisa; Cunha, Sara I.; Conze, Lei L.; O'Reilly, Nicola; Joshi, Dhira; Kjaer, Svend; George, Roger; Nye, Emma; Ma, Anqi; Jin, Jian; Mitter, Richard; Lupia, Michela; Cavallaro, Ugo; Pasini, Diego; Calado, Dinis P.; Dejana, Elisabetta; Taddei, Andrea.

In: Circulation Research, Vol. 122, No. 2, 01.01.2018, p. 231-245.

Research output: Contribution to journalArticle

Morini, MF, Giampietro, C, Corada, M, Pisati, F, Lavarone, E, Cunha, SI, Conze, LL, O'Reilly, N, Joshi, D, Kjaer, S, George, R, Nye, E, Ma, A, Jin, J, Mitter, R, Lupia, M, Cavallaro, U, Pasini, D, Calado, DP, Dejana, E & Taddei, A 2018, 'VE-cadherin-mediated epigenetic regulation of endothelial gene expression', Circulation Research, vol. 122, no. 2, pp. 231-245. https://doi.org/10.1161/CIRCRESAHA.117.312392
Morini, Marco F. ; Giampietro, Costanza ; Corada, Monica ; Pisati, Federica ; Lavarone, Elisa ; Cunha, Sara I. ; Conze, Lei L. ; O'Reilly, Nicola ; Joshi, Dhira ; Kjaer, Svend ; George, Roger ; Nye, Emma ; Ma, Anqi ; Jin, Jian ; Mitter, Richard ; Lupia, Michela ; Cavallaro, Ugo ; Pasini, Diego ; Calado, Dinis P. ; Dejana, Elisabetta ; Taddei, Andrea. / VE-cadherin-mediated epigenetic regulation of endothelial gene expression. In: Circulation Research. 2018 ; Vol. 122, No. 2. pp. 231-245.
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AU - Morini, Marco F.

AU - Giampietro, Costanza

AU - Corada, Monica

AU - Pisati, Federica

AU - Lavarone, Elisa

AU - Cunha, Sara I.

AU - Conze, Lei L.

AU - O'Reilly, Nicola

AU - Joshi, Dhira

AU - Kjaer, Svend

AU - George, Roger

AU - Nye, Emma

AU - Ma, Anqi

AU - Jin, Jian

AU - Mitter, Richard

AU - Lupia, Michela

AU - Cavallaro, Ugo

AU - Pasini, Diego

AU - Calado, Dinis P.

AU - Dejana, Elisabetta

AU - Taddei, Andrea

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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 β-catenin, which contribute to PRC2 (polycomb repressive complex-2) binding to promoter regions of claudin-5, VE-PTP, and vWf. VEC/β-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 VECnull 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.

AB - 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 β-catenin, which contribute to PRC2 (polycomb repressive complex-2) binding to promoter regions of claudin-5, VE-PTP, and vWf. VEC/β-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 VECnull 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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KW - Polycomb-group proteins

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