Derrett-Smith Emma C, Dooley Audrey, Gilbane Adrian J, Trinder Sarah L, Khan Korsa, Baliga Reshma, Holmes Alan M, Hobbs Adrian J, Abraham David, Denton Christopher P
University College London Medical School, Royal Free Campus, London, UK.
Arthritis Rheum. 2013 Nov;65(11):2928-39. doi: 10.1002/art.38078.
To delineate the constitutive pulmonary vascular phenotype of the TβRIIΔk-fib mouse model of scleroderma, and to selectively induce pulmonary endothelial cell injury using vascular endothelial growth factor (VEGF) inhibition to develop a model with features characteristic of pulmonary arterial hypertension (PAH).
The TβRIIΔk-fib mouse strain expresses a kinase-deficient transforming growth factor β (TGFβ) receptor type II driven by a fibroblast-specific promoter, leading to ligand-dependent up-regulation of TGFβ signaling, and replicates key fibrotic features of scleroderma. Structural, biochemical, and functional assessments of pulmonary vessels, including in vivo hemodynamic studies, were performed before and following VEGF inhibition, which induced pulmonary endothelial cell apoptosis. These assessments included biochemical analysis of the TGFβ and VEGF signaling axes in tissue sections and explanted smooth muscle cells.
In the TβRIIΔk-fib mouse strain, a constitutive pulmonary vasculopathy with medial thickening, a perivascular proliferating chronic inflammatory cell infiltrate, and mildly elevated pulmonary artery pressure resembled the well-described chronic hypoxia model of pulmonary hypertension. Following administration of SU5416, the pulmonary vascular phenotype was more florid, with pulmonary arteriolar luminal obliteration by apoptosis-resistant proliferating endothelial cells. These changes resulted in right ventricular hypertrophy, confirming hemodynamically significant PAH. Altered expression of TGFβ and VEGF ligand and receptor was consistent with a scleroderma phenotype.
In this study, we replicated key features of systemic sclerosis-related PAH in a mouse model. Our results suggest that pulmonary endothelial cell injury in a genetically susceptible mouse strain triggers this complication and support the underlying role of functional interplay between TGFβ and VEGF, which provides insight into the pathogenesis of this disease.
描绘硬皮病TβRIIΔk-fib小鼠模型的组成性肺血管表型，并使用血管内皮生长因子（VEGF）抑制选择性诱导肺内皮细胞损伤，以建立具有肺动脉高压（PAH）特征的模型。
TβRIIΔk-fib小鼠品系表达由成纤维细胞特异性启动子驱动的激酶缺陷型转化生长因子β（TGFβ）II型受体，导致TGFβ信号传导的配体依赖性上调，并复制硬皮病的关键纤维化特征。在VEGF抑制诱导肺内皮细胞凋亡之前和之后，对肺血管进行结构、生化和功能评估，包括体内血流动力学研究。这些评估包括组织切片和体外平滑肌细胞中TGFβ和VEGF信号轴的生化分析。
在TβRIIΔk-fib小鼠品系中，一种具有中膜增厚、血管周围增殖性慢性炎性细胞浸润和肺动脉压轻度升高的组成性肺血管病变类似于已充分描述的肺动脉高压慢性缺氧模型。给予SU5416后，肺血管表型更加明显，抗凋亡增殖内皮细胞导致肺小动脉管腔闭塞。这些变化导致右心室肥大，证实了血流动力学上显著的PAH。TGFβ和VEGF配体及受体的表达改变与硬皮病表型一致。
在本研究中，我们在小鼠模型中复制了系统性硬化症相关PAH的关键特征。我们的结果表明，基因易感小鼠品系中的肺内皮细胞损伤引发了这种并发症，并支持TGFβ和VEGF之间功能相互作用的潜在作用，这为该疾病的发病机制提供了见解。
