α2AP regulates vascular alteration by inhibiting VEGF signaling in systemic sclerosis: the roles of α2AP in vascular dysfunction in systemic sclerosis

نویسندگان

  • Yosuke Kanno
  • En Shu
  • Hiroyuki Kanoh
  • Ayaka Matsuda
  • Mariko Seishima
چکیده

BACKGROUND Systemic sclerosis (SSc) is a connective tissues disease of unknown origin characterized by vascular damage and extensive fibrosis. Recently, we demonstrated that α2-antiplasmin (α2AP) is associated with the development of fibrosis in SSc. We herein investigate the roles of α2AP in vascular dysfunction in SSc. METHODS Vascular damage in mice was determined by the levels of blood vessels and blood flow. Vascular functions in vascular endothelial cells (ECs) were determined by the levels of tube formation, cell proliferation, and endothelial junction-associated protein (VE-cadherin and PECAM1) production. RESULTS The administration of α2AP induced vascular damage in mice. Conversely, the α2AP neutralization improved vascular damage in a bleomycin-induced mouse model of SSc. Additionally, we showed that the SSc fibroblast-conditioned media induced the reduction of tube formation, cell proliferation, and endothelial junction-associated protein production in ECs, and that α2AP neutralization improved them. We also examined the mechanisms underlying the effects of α2AP on vascular alteration in SSc and found that α2AP attenuated vascular endothelial growth factor-induced tube formation, cell proliferation, and endothelial junction-associated protein production through the adipose triglyceride lipase/tyrosine phosphatase SHP2 axis in ECs. CONCLUSION Our findings demonstrate that α2AP is associated with vascular alteration, and that the blocking of α2AP improves vascular dysfunction in SSc.

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عنوان ژورنال:

دوره 19  شماره 

صفحات  -

تاریخ انتشار 2017