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Scleroderma dermal fibroblasts overexpress vascular endothelial growth factor due to autocrine transforming growth factor β signaling
Modern Rheumatology, 07/11/2012
Kajihara I et al. – The authors demonstrated that vascular endothelial growth factor (VEGF) were overexpressed due to autocrine TGF–Β/Smad signaling in scleroderma (SSc). TGF–Β signaling may contribute to the pathogenesis of angiopathy as well as tissue fibrosis.
Methods- Protein and mRNA levels of VEGF were analyzed using immunoblotting, enzyme–linked immunosorbent assay, and real–time PCR.
- The DNA–binding ability of Smad3 was evaluated by DNA affinity precipitation.
- VEGF mRNA expression in vivo was increased in SSc skin compared to skin with other collagen diseases.
- Expression of VEGF protein and mRNA in cultured SSc dermal fibroblasts was constitutively and significantly upregulated.
- Ectopic TGF–β stimulation induced VEGF synthesis in normal fibroblasts, and TGF–β knockdown normalized the upregulated VEGF levels in SSc fibroblasts.
- Furthermore, Smad3 overexpression induced VEGF levels.
- They found that bp –532 to –521 on the VEGF promoter is a putative binding site for Smads, and that the binding activity of Smad3 to VEGF promoter was constitutively increased in SSc fibroblasts as well as in normal fibroblasts treated with exogenous TGF–β1.
