Impaired angiogenesis in systemic sclerosis: the emerging role of the antiangiogenic VEGF(165)b splice variant

Trends Cardiovasc Med. 2011 Oct;21(7):204-10. doi: 10.1016/j.tcm.2012.05.011.


Systemic sclerosis (SSc, or scleroderma) is a chronic, multisystem connective tissue disorder characterized by widespread microvascular damage, fibrosis, and autoimmunity that affects the skin and internal organs. In the course of SSc, chronic tissue ischemia and lack of compensatory angiogenesis may lead to loss of dermal capillaries and arterioles and severe peripheral vascular complications, such as nonhealing digital ulcers and, occasionally, gangrene of the extremities, which represent a heavy burden due to their major impact on patients' quality of life. Surprisingly, several studies published during the past decade showed that the potent proangiogenic mediator vascular endothelial growth factor-A (VEGF-A) is overexpressed in the skin and circulation of patients with SSc despite evidence of an overall insufficient angiogenic response. However, early studies could not make the distinction between proangiogenic VEGF(165) and antiangiogenic VEGF(165)b isoforms, which have been uncovered only recently and appear to be generated by alternative splicing mechanisms in the terminal exon of VEGF-A pre-mRNA. In a recent study, we provided the first evidence that a switch from proangiogenic to antiangiogenic VEGF-A isoforms may play a crucial role in the defective angiogenic and vascular repair processes that characterize SSc. Future clinical and translational research should address whether molecular regulation of VEGF-A pre-mRNA splicing might represent a potential therapeutic strategy for the SSc-related peripheral vasculopathy and, most widely, for other pathologic conditions in humans in which we seek to promote or inhibit angiogenesis.

Publication types

  • Review

MeSH terms

  • Autoimmunity / genetics
  • Fibrosis / pathology
  • Humans
  • Neovascularization, Pathologic / pathology*
  • RNA, Messenger / genetics
  • Scleroderma, Systemic / genetics*
  • Scleroderma, Systemic / pathology
  • Vascular Endothelial Growth Factor A / genetics*


  • RNA, Messenger
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A