Cyclophosphamide pulse therapy normalizes vascular abnormalities in a mouse model of systemic sclerosis vasculopathy

Intravenous cyclophosphamidepulse, a standard treatment for systemic sclerosis (SSc)-related interstitial lung disease, elicits a disease-modifying effect on SSc vasculopathy, such as fostering microvascular de-remodeling. To investigate the molecular mechanism by which cyclophosphamidemitigates SSc vasculopathy, we employed endothelial cell–specific Fli1knockout mice that mimic the functional and structural vascular abnormalities characteristic of SSc. Biweekly cyclophosphamideinjection improved vascular permeabilityand structural abnormalities of endothelial cell–specific Fli1knockout mice in 2 weeks and in 3 months, respectively. In endothelial cell–specific Fli1knockout mice, a single dose of cyclophosphamidewas sufficient to normalize the decreased expression of α–smooth muscle actin in dermal blood vessels and improve the impaired neovascularization in skin-embedded Matrigelplug. Under the same condition, the decreased expression of vascular endothelial cadherin, platelet-derived growth factorB, S1P 1 , and CCN1 (molecules associated with angiogenesis and/or vasculogenesis) was reversed along with the reversal of endothelial Fli1expression. In SSc patients, serum CCN1 levels were significantly increased after intravenous cyclophosphamidepulse. Taken together, these results indicate that cyclophosphamideimproves Fli1deficiency-dependent vascular changes by normalizing the expression of angiogenesis- and vasculogenesis-related molecules and endothelial Fli1, which may help to explain the beneficial effect of cyclophosphamideon SSc vasculopathy.