Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
J Invest Dermatol. 2019 May;139(5):1150-1160. doi: 10.1016/j.jid.2018.11.016. Epub 2018 Nov 30.
Intravenous cyclophosphamide pulse, 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 cyclophosphamide mitigates SSc vasculopathy, we employed endothelial cell-specific Fli1 knockout mice that mimic the functional and structural vascular abnormalities characteristic of SSc. Biweekly cyclophosphamide injection improved vascular permeability and structural abnormalities of endothelial cell-specific Fli1 knockout mice in 2 weeks and in 3 months, respectively. In endothelial cell-specific Fli1 knockout mice, a single dose of cyclophosphamide was sufficient to normalize the decreased expression of α-smooth muscle actin in dermal blood vessels and improve the impaired neovascularization in skin-embedded Matrigel plug. Under the same condition, the decreased expression of vascular endothelial cadherin, platelet-derived growth factor B, S1P, and CCN1 (molecules associated with angiogenesis and/or vasculogenesis) was reversed along with the reversal of endothelial Fli1 expression. In SSc patients, serum CCN1 levels were significantly increased after intravenous cyclophosphamide pulse. Taken together, these results indicate that cyclophosphamide improves Fli1 deficiency-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 cyclophosphamide on SSc vasculopathy.
静脉注射环磷酰胺脉冲是治疗系统性硬化症（SSc）相关间质性肺病的标准治疗方法，它对 SSc 血管病变具有疾病修饰作用，例如促进微血管去重构。为了研究环磷酰胺减轻 SSc 血管病变的分子机制，我们使用了内皮细胞特异性 Fli1 敲除小鼠，该小鼠模拟了 SSc 特征性的功能性和结构性血管异常。每周两次的环磷酰胺注射分别在 2 周和 3 个月改善了内皮细胞特异性 Fli1 敲除小鼠的血管通透性和结构异常。在内皮细胞特异性 Fli1 敲除小鼠中，单次环磷酰胺剂量足以使皮肤血管中减少的α-平滑肌肌动蛋白表达正常化，并改善皮肤嵌入 Matrigel 塞中的受损新生血管化。在相同条件下，血管内皮钙黏蛋白、血小板衍生生长因子 B、S1P 和 CCN1（与血管生成和/或血管发生相关的分子）的表达减少得到逆转，同时内皮 Fli1 表达也得到逆转。在 SSc 患者中，静脉注射环磷酰胺脉冲后血清 CCN1 水平显著升高。综上所述，这些结果表明，环磷酰胺通过使血管生成和血管发生相关分子和内皮 Fli1 的表达正常化，改善了 Fli1 缺乏依赖性的血管变化，这可能有助于解释环磷酰胺对 SSc 血管病变的有益作用。
