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Endothelial-to-mesenchymal transition contributes to endothelial dysfunction and dermal fibrosis in systemic sclerosis
  1. Mirko Manetti1,
  2. Eloisa Romano2,
  3. Irene Rosa1,2,
  4. Serena Guiducci2,
  5. Silvia Bellando-Randone2,
  6. Amato De Paulis3,
  7. Lidia Ibba-Manneschi1,
  8. Marco Matucci-Cerinic2
  1. 1Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, University of Florence, Florence, Italy
  2. 2Department of Experimental and Clinical Medicine, Section of Internal Medicine, Rheumatology Unit, Azienda Ospedaliero-Universitaria Careggi (AOUC), University of Florence, Florence, Italy
  3. 3Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research, University of Naples Federico II, Naples, Italy
  1. Correspondence to Dr Mirko Manetti, Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, University of Florence, Largo Brambilla 3, Florence 50134, Italy; mirkomanetti{at}, mirko.manetti{at}


Objective Systemic sclerosis (SSc) features multiorgan fibrosis orchestrated predominantly by activated myofibroblasts. Endothelial-to-mesenchymal transition (EndoMT) is a transdifferentiation by which endothelial cells (ECs) lose their specific morphology/markers and acquire myofibroblast-like features. Here, we determined the possible contribution of EndoMT to the pathogenesis of dermal fibrosis in SSc and two mouse models.

Methods Skin sections were immunostained for endothelial CD31 or vascular endothelial (VE)-cadherin in combination with α-smooth muscle actin (α-SMA) myofibroblast marker. Dermal microvascular ECs (dMVECs) were prepared from SSc and healthy skin (SSc-dMVECs and H-dMVECs). H-dMVECs were treated with transforming growth factor-β1 (TGFβ1) or SSc and healthy sera. Endothelial/mesenchymal markers were assessed by real-time PCR, immunoblotting and immunofluorescence. Cell contractile phenotype was assayed by collagen gel contraction.

Results Cells in intermediate stages of EndoMT were identified in dermal vessels of either patients with SSc or bleomycin-induced and urokinase-type plasminogen activator receptor (uPAR)-deficient mouse models. At variance with H-dMVECs, SSc-dMVECs exhibited a spindle-shaped appearance, co-expression of lower levels of CD31 and VE-cadherin with myofibroblast markers (α-SMA+ stress fibres, S100A4 and type I collagen), constitutive nuclear localisation of the EndoMT driver Snail1 and an ability to effectively contract collagen gels. Treatment of H-dMVECs either with SSc sera or TGFβ1 resulted in the acquisition of a myofibroblast-like morphology and contractile phenotype and downregulation of endothelial markers in parallel with the induction of mesenchymal markers. Matrix metalloproteinase-12-dependent uPAR cleavage was implicated in the induction of EndoMT by SSc sera.

Conclusions In SSc, EndoMT may be a crucial event linking endothelial dysfunction and development of dermal fibrosis.

  • Systemic Sclerosis
  • Qualitative research
  • Fibroblasts

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  • Handling editor Tore K Kvien

  • Contributors Study conception and design: MM, ER, LI-M and MM-C. Acquisition of data: MM, ER, IR, SG, SB-R, ADP, LI-M and MM-C. Interpretation of data: MM, ER, IR, LI-M and MM-C. Manuscript preparation: MM and MM-C.

  • Funding Supported by grants from the University of Florence (Progetti di Ricerca di Ateneo to LI-M and MM-C).

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval The study was approved by the local institutional review board at the Azienda Ospedaliero-Universitaria Careggi (AOUC), Florence, Italy.

  • Provenance and peer review Not commissioned; externally peer reviewed.