systemic vasculopathy with altered vasoreactivity in a transgenic mouse model of scleroderma系统性血管病变与改变vasoreactivity硬皮病的转基因小鼠模型.pdf

Derrett-Smith et al. Arthritis Research Therapy 2010, 12:R69 /content/12/2/R69 R E S E A R C H A R T I C L E Open Access Research article Systemic vasculopathy with altered vasoreactivity in a transgenic mouse model of scleroderma Emma C Derrett-Smith, Audrey Dooley, Korsa Khan, Xu Shi-wen, David Abraham and Christopher P Denton* Abstract Introduction: Vasculopathy, including altered vasoreactivity and ab normal large vessel biomechanics, is a hallmark of systemic sclerosis (SSc). However, the pathogenic link with other aspects of the disease is less clear. To assess the potential role of transforming growth factor beta (TGF-β) overactivity in driving these cardiovascular abnormalities, we studied a novel transgenic mouse model characterized by ligand-dependent activation of TGF-β signaling in fibroblasts. Methods: The transgenic mouse strain Tβ RIIΔk-fib is characterized by balanced ligand-dependent upregulation of TGF-β signaling. Aortic and cardiac tissues were examined with histologic, biochemical, and isolated organ bath studies. Vascular and perivascular architecture was examined by hematoxylin and eosin (HE) and special stains including immunostaining for TGF-β1 and phospho-Smad2/3 (pSmad2/3). Confirmatory aortic smooth muscle cell proliferation, phenotype, and functional assays, including signaling responses to exogenous TGF-β and endothelin-1, were performed. Aortic ring contractile responses to direct and receptor-mediated stimulation were assessed. Results: Aortic ring contractility and relaxation were diminished compared with wild-type controls, and this was associated with aortic adventitial fibrosis confirmed histologically and with Sircol assay. TGF-β1 and pSmad 2/3 expression was increased in the adventitia and smooth muscle layer of the aorta. Aortic smooth muscle cells from transgenic animals showed s