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Increased plasma levels of the VEGF165b splice variant are associated with the severity of nailfold capillary loss in systemic sclerosis
  1. Mirko Manetti1,2,
  2. Serena Guiducci2,
  3. Eloisa Romano2,
  4. Silvia Bellando-Randone2,
  5. Gemma Lepri2,
  6. Cosimo Bruni2,
  7. Maria Letizia Conforti2,
  8. Lidia Ibba-Manneschi1,
  9. 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 and Division of Rheumatology, Azienda Ospedaliero-Universitaria Careggi, University of Florence, Florence, 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 I-50134, Italy; mirkomanetti{at} MM and SG contributed equally to this work.

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In systemic sclerosis (SSc), Raynaud's phenomenon is the earliest clinical manifestation paralleled by nailfold capillaroscopic alterations that may occur months or even years before the onset of fibrosis.1 This evidence suggests a crucial role of microangiopathy characterised by a progressive loss of capillaries with the formation of avascular areas.1 ,2 Consequent chronic tissue hypoxia leads to skin ulcers and gangrene that heavily burden patients’ quality of life.1 ,2 Vascular endothelial growth factor-A (VEGF-A) is overexpressed in SSc skin, and increased circulating levels of VEGF-A correlate with the severity of nailfold capillary loss.2–4 It has been demonstrated that the VEGF-A primary transcript can be alternatively spliced in its terminal exon, producing two distinct mRNA splice variants that are translated to the proangiogenic VEGF165 and antiangiogenic VEGF165b isoforms.5 These two isoforms bind to the tyrosine kinase receptor VEGFR-2 with the same affinity, but binding of VEGF165b results in an insufficient tyrosine phosphorylation/activation of VEGFR-2 and incomplete or transient downstream signalling, which lead to an impaired angiogenic response.5 ,6 Recently, we have provided the first evidence that dermal expression and plasma levels of VEGF165b are raised in SSc patients, and VEGF165b overexpression prevents SSc dermal microvascular endothelial …

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