Angiotensin II induced skin fibrosis in mice is associated with vascular injury

Abstract

We recently reported that Ang II induces skin fibrosis in mice (Stawski et al, 2012). The goal of this study was to further investigate the mechanisms involved in skin fibrosis induced by Ang II as a model for the pathogenic mechanisms of Scleroderma. Ang II was administered to mice for 7 and 14 days by subcutaneous osmotic pump. TUNEL and cleaved Caspase 3 staining showed increased number of apoptotic cells present in the vessels and in the connective tissue in Ang II treated mice. IHC staining showed increased number of Mmp12‐positive cells, including ECs in Ang II infused mice. MMP12 protein level was increased in Ang II treated human MVECs in a dose dependant manner. Pdgfrb‐positive cells were observed around the vessels in control mice, but were increased in all skin layers in Ang II mice. Real‐time PCR analysis showed a statistically significant increase in the levels of vascular injury markers: Angpt2 at day 7, Mmp12 and Thbs1 at day 14 and pericyte marker Adam12 at day 7 in the skin of Ang II infused mice.These observations together with the previously reported data strongly suggest that the Ang II model closely reproduces one of the key features of SSc ‐ vascular injury. Moreover, persistent defect of endothelial cells in this model may lead to development of a chronic fibrogenic environment resulting in activation of peri‐endothelial cells that leads to fibrosis.