Endothelial Fli1 deficiency impairs vascular homeostasis: a role in scleroderma vasculopathy.
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.
Arthritis Center, Boston University Medical Center, Boston, MA 02118, USA.
Yoshihide
Y
Asano
Lukasz
L
Stawski
Faye
F
Hant
Kristin
K
Highland
Richard
R
Silver
Gabor
G
Szalai
Dennis K
DK
Watson
Maria
M
Trojanowska
D000199:Actins / Q000378:metabolism; D000483:Alleles; D000818:Animals; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D008833:Microcirculation; D010539:Permeability; D010641:Phenotype; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics* / Q000502:physiology; D012595:Scleroderma, Systemic / Q000378:metabolism*; D012867:Skin / Q000473:pathology; D014652:Vascular Diseases / Q000473:pathology*
D000199:Actins; C078433:FLI1 protein, human; C497426:Fli1 protein, mouse; D051789:Proto-Oncogene Protein c-fli-1