Abstract
Neointimal lesion and medial wall thickness of pulmonary arteries (PAs) are common pathological findings in pulmonary arterial hypertension (PAH). Platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) signaling contribute to intimal and medial vascular remodeling in PAH. Nintedanib is a tyrosine kinase inhibitor whose targets include PDGF and FGF receptors. Although the beneficial effects of nintedanib were demonstrated for human idiopathic pulmonary fibrosis, its efficacy for PAH is still unclear. Thus, we hypothesized that nintedanib is a novel treatment for PAH to inhibit the progression of vascular remodeling in PAs. We evaluated the inhibitory effects of nintedanib both in endothelial mesenchymal transition (EndMT)-induced human pulmonary microvascular endothelial cells (HPMVECs) and human pulmonary arterial smooth muscle cells (HPASMCs) stimulated by growth factors. We also tested the effect of chronic nintedanib administration on a PAH rat model induced by Sugen5416 (a VEGF receptor inhibitor) combined with chronic hypoxia. Nintedanib was administered from weeks 3 to 5 after Sugen5416 injection, and we evaluated pulmonary hemodynamics and PAs pathology. Nintedanib attenuated the expression of mesenchymal markers in EndMT-induced HPMVECs and HPASMCs proliferation. Phosphorylation of PDGF and FGF receptors was augmented in both intimal and medial lesions of PAs. Nintedanib blocked these phosphorylation, improved hemodynamics and reduced vascular remodeling involving neointimal lesions and medial wall thickening in PAs. Additionally, expressions Twist1, transcription factors associated with EndMT, in lung tissue was significantly reduced by nintedanib. These results suggest that nintedanib may be a novel treatment for PAH with anti-vascular remodeling effects.
Highlights
The pathogenesis of pulmonary arterial hypertension (PAH) involves abnormal vasoconstriction and vascular remodeling in pulmonary arteries (PAs)
The viability of human pulmonary arterial smooth muscle cells (HPASMCs) was evaluated time-dependently after stimulation. In advance of this assay, we examined the concentration-dependent inhibitory effects of nintedanib and imatinib, the latter of which is another tyrosine kinase inhibitor (TKI) for platelet derived growth factor (PDGF) signaling, on the proliferation of HPASMCs induced by PDGF-BB
The proliferation of HPASMCs induced by multiple growth factors (PDGF-BB, FGF2, epidermal growth factor (EGF), and IGF) was significantly greater than that without stimulation in Cell Counting Kit-8 (CCK-8) and BrdU assays, and nintedanib significantly inhibited this proliferation at 24 and 48 h after stimulation
Summary
The pathogenesis of pulmonary arterial hypertension (PAH) involves abnormal vasoconstriction and vascular remodeling in pulmonary arteries (PAs). EndMT-modified endothelial cells acquire additional characteristics of mesenchymal cells, and recent reports have indicated a critical role of EndMT in the development of PAH-specific neointimal lesions in PAs [11,12,13]. Both medial wall thickening and neointimal lesions in PAs are common pathological findings in PAH, a greater contribution of neointimal lesions in the elevation of pulmonary arterial pressure was reported in experimental PAH [14], suggesting an important involvement of EndMT
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