Vascular alterations upon activation of TGFβ signaling in fibroblasts - implications for systemic sclerosis

Using the TβRIIΔk-fib transgenic mouse model, Derrett-Smith and colleagues [1] analyzed a potential role of transforming growth factor β (TGFβ) signaling in the vascular pathogenesis of systemic sclerosis (SSc).SSc is a chronic autoimmune disease that affects the skin and various internal organs. The most obvious histopathological alteration of SSc is an extensive accumulation of extracellular matrix [2]. The resulting fibrosis disrupts the physiological tissue structure and frequently leads to dysfunction of the affected organs. The accumulation of extracellular matrix in SSc patients is caused by activated fibroblasts [3]. In addition to fibrosis, vascular changes are a major hallmark of SSc. These may be classified into a destructive- and a proliferative vasculopathy. The destructive vasculopathy affects small vessels and manifests early in the course of SSc as progressive loss of capillaries and insufficient angiogenesis. The clinical correlates of the destructive vasculopathy are Raynaud's phenomenon and fingertip ulcers. In contrast, the proliferative vasculopathy is characterized by proliferation of vascular cells with obstruction of the lumen, affects larger vessels like the pulmonary arteries and often manifests later in the course of the disease as pulmonary arterial hypertension [2].The key-role of TGFβ in fibrosis is well established as TGFβ signaling is activated in SSc. Activated TGFβ signaling stimulates the release of collagen in cultured fibroblasts and overexpression of a constitutively active TGFβ receptor type I in fibroblasts results in progressive fibrosis [3]. Moreover, inhibition of TGFβ signaling exerted potent anti-fibrotic effects in different preclinical models of SSc [4].In contrast to fibrosis, only few data suggest a role of TGFβ in the vascular pathogenesis of SSc. First data from mouse models suggest that aberrant TGFβ signaling might not result in only fibrosis, but also in vascular alterations. Vascular changes have been described