title: Impaired Cav-1 expression in SSc mesenchymal cells upregulates VEGF signaling: a link between vascular involvement and fibrosis.
abstract: BACKGROUND
  Systemic sclerosis (SSc) is characterized by vascular alteration and fibrosis, the former probably leading to fibrosis via the ability of both endothelial cells and pericytes to differentiate toward myofibroblast. It is well known that vascular endothelial growth factor A (VEGF-A, hereafter referred to as VEGF) may induce a profibrotic phenotype on perivascular cells. Caveolin-1 (Cav-1) is involved in the regulation of VEGF signaling, playing a role in the transport of internalized VEGF receptor 2 (VEGFR2) toward degradation, thus decreasing VEGF signaling. In this work, we assessed the levels of Cav-1 in SSc bone marrow mesenchymal stem cells (SSc-MSCs), a pericyte surrogate, and correlate these results with VEGF signaling, focusing onpotential pathogenic pathways leading to fibrosis.
  
  
  RESULTS
  WE EXPLORED THE VEGF SIGNALING ASSESSING: (1) Cav-1 expression; (2) its co-localization with VEGFR2; (3) the activity of VEGFR2, by IF, immunoprecipitation, and western blot. In SSc-MSCs, Cav-1 levels were lower when compared to healthy controls (HC)-MSCs. Furthermore, the Cav-1/VEGFR2 co-localization and the ubiquitination of VEGFR2 were impaired in SSc-MSCs, suggesting a decreased degradation of the receptor and, as a consequence, the tyrosine phosphorylation of VEGFR2 and the PI3-kinase-Akt pathways were significantly increased when compared to HC. Furthermore, an increased connective tissue growth factor (CTGF) expression was observed in SSc-MSCs. Taken together, these data suggested the upregulation of VEGF signaling in SSc-MSCs. Furthermore, after silencing Cav-1 expression in HC-MSCs, an increased CTGF expression in HC-MSCs was observed, mirroring the results obtained in SSc-MSCs, and confirming the potential role that the lack of Cav-1 may play in the persistent VEGF signaling .
  
  
  CONCLUSIONS
  During SSc, the lower levels of Cav-1 may contribute to the pathogenesis of fibrosis via an upregulation of the VEGF signaling in perivascular cells which are shifted to a profibrotic phenotype.
authors.affiliation: Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila, Delta 6 Building, Via dell'Ospedale, 67100 L'Aquila, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Cipriani
authors.affiliation: Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila, Delta 6 Building, Via dell'Ospedale, 67100 L'Aquila, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Di Benedetto
authors.affiliation: Department of Applied Clinical Sciences and Biotechnology, University of L'Aquila, Coppito 2, 67100 L'Aquila, Italy.
authors.forename: Daria
authors.initials: D
authors.lastname: Capece
authors.affiliation: Department of Applied Clinical Sciences and Biotechnology, University of L'Aquila, Coppito 2, 67100 L'Aquila, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Zazzeroni
authors.affiliation: Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila, Delta 6 Building, Via dell'Ospedale, 67100 L'Aquila, Italy.
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Liakouli
authors.affiliation: Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila, Delta 6 Building, Via dell'Ospedale, 67100 L'Aquila, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Ruscitti
authors.affiliation: Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila, Delta 6 Building, Via dell'Ospedale, 67100 L'Aquila, Italy.
authors.forename: Ilenia
authors.initials: I
authors.lastname: Pantano
authors.affiliation: Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila, Delta 6 Building, Via dell'Ospedale, 67100 L'Aquila, Italy.
authors.forename: Onorina
authors.initials: O
authors.lastname: Berardicurti
authors.affiliation: Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila, Delta 6 Building, Via dell'Ospedale, 67100 L'Aquila, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Carubbi
authors.affiliation: Department of Applied Clinical Sciences and Biotechnology, University of L'Aquila, Coppito 2, 67100 L'Aquila, Italy.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Alesse
authors.affiliation: Department of Applied Clinical Sciences and Biotechnology, Rheumatology Unit, School of Medicine, University of L'Aquila, Delta 6 Building, Via dell'Ospedale, 67100 L'Aquila, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Giacomelli
keywords: Caveolin-1; Mesenchymal stem cells; Pericytes; Systemic sclerosis