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Decreased expression of neuropilin-1 as a novel key factor contributing to peripheral microvasculopathy and defective angiogenesis in systemic sclerosis
  1. Eloisa Romano1,
  2. Inês Chora1,2,
  3. Mirko Manetti3,
  4. Celestina Mazzotta1,
  5. Irene Rosa1,3,
  6. Silvia Bellando-Randone1,
  7. Jelena Blagojevic1,
  8. Raquel Soares4,
  9. Jerôme Avouac5,
  10. Yannick Allanore5,
  11. Lidia Ibba-Manneschi3,
  12. Marco Matucci-Cerinic1,
  13. Serena Guiducci1
  1. 1Department of Experimental and Clinical Medicine, Division of Rheumatology, Azienda Ospedaliero-Universitaria Careggi (AOUC), University of Florence, Florence, Italy
  2. 2Department of Internal Medicine, São João Hospital Center, Porto, Portugal
  3. 3Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, University of Florence, Florence, Italy
  4. 4Department of Biochemistry, Faculty of Medicine, University of Porto, Porto, Portugal
  5. 5Cochin Institute, Paris Descartes University, INSERM U1016 and CNRS UMR8104, Paris, France
  1. Correspondence to Dr Eloisa Romano, Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Florence, Viale Pieraccini 6, Florence 50139, Italy; eloisaromano{at}libero.it

Abstract

Objectives In systemic sclerosis (SSc), vascular involvement is characterised by vascular endothelial growth factor (VEGF)-A/VEGF receptor (VEGFR) system disturbances. Neuropilin-1 (NRP1), a receptor for both class-3 semaphorins (Sema3s) and VEGF-A, is required for optimal VEGF-A/VEGFR-2 signalling. Here, we investigated the possible involvement of Sema3A/NRP1 axis in SSc.

Methods Circulating Sema3A and soluble NRP1 (sNRP1) were measured in patients with SSc and controls. NRP1 and Sema3A expression in skin biopsies was evaluated by immunofluorescence and western blotting. NRP1 expression was assessed in SSc and healthy dermal microvascular endothelial cells (SSc-MVECs and H-MVECs), and in SSc and control endothelial progenitor cell (EPC)-derived endothelial cells (ECs). The possible impact of transcription factor Friend leukaemia integration 1 (Fli1) deficiency on endothelial NRP1 expression was investigated by gene silencing. The binding of Fli1 to NRP1 gene promoter was evaluated using chromatin immunoprecipitation. Capillary morphogenesis was performed on Matrigel.

Results Decreased sNRP1 levels in SSc were associated with active and late nailfold videocapillaroscopy patterns and digital ulcers. No difference in Sema3A was found between patients and controls. NRP1 was significantly decreased in SSc-MVECs both ex vivo and in vitro. NRP1 and Fli1 significantly decreased in H-MVECs challenged with SSc sera, while they were not different in SSc and control EPC-derived ECs. Fli1 occupied the NRP1 gene promoter and Fli1 gene silencing reduced NRP1 expression in H-MVECs. NRP1 gene silencing in H-MVECs resulted in a significantly impaired angiogenic capacity comparable to that of cells treated with SSc sera.

Conclusion In SSc, NRP1 deficiency may be an additional factor in the perturbed VEGF-A/VEGFR-2 system contributing to peripheral microvasculopathy and defective angiogenesis.

  • Systemic Sclerosis
  • Autoimmune Diseases
  • Qualitative research

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