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Cellular and molecular aspects of vascular dysfunction in systemic sclerosis

Nature Reviews Rheumatology volume 6, pages 453–460 (2010)Cite this article

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Abstract

Systemic sclerosis (SSc) is characterized by vascular alterations, activation of the immune system and tissue fibrosis. Vascular insufficiency manifests early in the disease, and although there is evidence of an active repair process, capillaries deteriorate and regress. Factors that contribute to the failure of vascular regeneration might include persistent injury, an imbalance between proangiogenic and antiangiogenic mediators, intrinsic abnormal properties of the cellular components of the vessels, and the presence of fibroblast-derived antiangiogenic factors. In addition, circulating dysfunctional endothelial progenitor cells might further exacerbate vessel deterioration. Abnormal expression of transcription factors, including Fra2 and Fli1, has been proposed to contribute to SSc vasculopathy. Fli1 regulates genes that are involved in vessel maturation and stabilization, suggesting that reduced levels of Fli1 in SSc vasculature could contribute to the development of unstable vessels that are prone to regression. Conversely, proliferating endothelial cells and pericytes, in the presence of an appropriate stimulus, might transdifferentiate into collagen-producing cells, and thus contribute to the initiation of fibrosis. Despite progress in treating the symptoms of vascular disease in SSc, the underlying mechanisms remain poorly understood. An improved knowledge of the molecular and cellular pathways that contribute to SSc vasculopathy could help in the design of effective therapies in the future.

Key Points

  • Systemic sclerosis (SSc) is initiated by endothelial cell injury; this event leads to progressive structural defects in microvessels

  • There is evidence of enhanced angiogenic activity early in the disease

  • Multiple factors might contribute to defective vascular repair and regeneration

  • Intrinsic pathogenic alterations in endothelial cells might be a key factor that interferes with the vascular repair process

  • Aberrant expression of endothelial transcription factors, including Fra2, Fli1, peroxisome proliferator-activated receptor γ and GATA-6, has been associated with SSc, and might contribute to vascular defects

  • Endothelial cells and pericytes could represent a source of activated fibroblasts early in the disease

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Figure 1: Schematic overview of the principal stages of angiogenesis.
Figure 2: Schematic overview of the potential mechanisms involved in impaired neoangiogenesis in SSc.
Figure 3: Molecular alterations of components of the SSc vasculature.
Figure 4: Possible links between vasculopathy and fibrosis in SSc.

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  1. Boston University School of Medicine, Arthritis Center, 72 East Concord Street, Evans 501, Boston, 02118, MA, USA

    Maria Trojanowska

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Trojanowska, M. Cellular and molecular aspects of vascular dysfunction in systemic sclerosis. Nat Rev Rheumatol 6, 453–460 (2010). https://doi.org/10.1038/nrrheum.2010.102

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