Endothelial Fli1 deficiency impairs vascular homeostasis: a role in scleroderma vasculopathy

Am J Pathol. 2010 Apr;176(4):1983-98. doi: 10.2353/ajpath.2010.090593. Epub 2010 Mar 12.


Systemic sclerosis or scleroderma (SSc) is a complex autoimmune connective tissue disease characterized by obliterative vasculopathy and tissue fibrosis. The molecular mechanisms underlying SSc vasculopathy are largely unknown. Friend leukemia integration factor 1 (Fli1), an important regulator of immune function and collagen fibrillogenesis, is expressed at reduced levels in endothelial cells in affected skin of patients with SSc. To develop a disease model and to investigate the function of Fli1 in the vasculature, we generated mice with a conditional deletion of Fli1 in endothelial cells (Fli1 CKO). Fli1 CKO mice showed a disorganized dermal vascular network with greatly compromised vessel integrity and markedly increased vessel permeability. We show that Fli1 regulates expression of genes involved in maintaining vascular homeostasis including VE-cadherin, platelet endothelial cell adhesion molecule 1, type IV collagen, matrix metalloproteinase 9, platelet-derived growth factor B, and S1P(1) receptor. Accordingly, Fli1 CKO mice are characterized by down-regulation of VE-cadherin and platelet endothelial cell adhesion molecule 1, impaired development of basement membrane, and a decreased presence of alpha-smooth muscle actin-positive cells in dermal microvessels. This phenotype is consistent with a role of Fli1 as a regulator of vessel maturation and stabilization. Importantly, vascular characteristics of Fli1 CKO mice are recapitulated by SSc microvasculature. Thus, persistently reduced levels of Fli1 in endothelial cells may play a critical role in the development of SSc vasculopathy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Alleles
  • Animals
  • Humans
  • Immunohistochemistry / methods
  • Mice
  • Mice, Knockout
  • Microcirculation
  • Permeability
  • Phenotype
  • Proto-Oncogene Protein c-fli-1 / genetics*
  • Proto-Oncogene Protein c-fli-1 / physiology
  • Scleroderma, Systemic / metabolism*
  • Skin / pathology
  • Vascular Diseases / pathology*


  • Actins
  • FLI1 protein, human
  • Fli1 protein, mouse
  • Proto-Oncogene Protein c-fli-1