Endothelial injury in a TGFβ dependent mouse model of scleroderma induces pulmonary arterial hypertension.
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Objective: To delineate the constitutive pulmonary vascular phenotype of the TβRIIΔk-fib mouse model of scleroderma and selectively induce pulmonary endothelial cell injury using VEGF inhibition to develop a model with features characteristic of pulmonary arterial hypertension. Methods: The TβRIIΔk-fib mouse strain expresses a kinase-deficient type II TGFβ receptor driven by a fibroblast-specific promoter leading to ligand-dependent upregulation of TGFβ signaling and replicates key fibrotic features of scleroderma. Structural, biochemical and functional assessments of pulmonary vessels including in vivo haemodynamic studies were performed before and following VEGF inhibition, which induced pulmonary endothelial cell apoptosis. These included biochemical analysis of the TGFβ and VEGF signaling axes in tissue sections and explanted smooth muscle cells. Results: 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 pressures resembles 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 (transgenic RV mass index 0.25±0.03, wildtype 0.15±0.01, p<0.01) confirming haemodynamically significant pulmonary arterial hypertension. Altered TGFβ and VEGF ligand and receptor expression were consistent with a scleroderma phenotype. Conclusion This study replicates key features of scleroderma-associated pulmonary arterial hypertension in a mouse model. Our results suggest that pulmonary endothelial cell injury in a genetically-susceptible mouse strain triggers this complication and support functional interplay between TGFβ and VEGF that provides insight into pathogenesis. © 2013 American College of Rheumatology.
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