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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 …
Contributors All authors were involved in drafting the article or revising it critically for important intellectual content and all authors approved the final version to be published. Study conception and design: MM, SG, ER, LI-M and MM-C. Acquisition of data: MM, SG, ER, SB-R, GL, CB, MLC and MM-C. Analysis and interpretation of data: MM, SG, ER, SB-R, GL, CB, LI-M and MM-C.
Funding This study has been supported by grants from the University of Florence (Progetti di Ricerca di Ateneo to MM-C).
Competing interests None.
Patient consent Obtained.
Ethics approval The study was approved by the institutional review board. All subjects gave written informed consent.
Provenance and peer review Not commissioned; externally peer reviewed.