Nintedanib ameliorates experimental pulmonary arterial hypertension via inhibition of endothelial mesenchymal transition and smooth muscle cell proliferation

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. The inhibitory effects of nintedanib were evaluated 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 pulmonary hemodynamics and PAs pathology were evaluated. Nintedanib attenuated the expression of mesenchymal markers in EndMT-induced HPMVECs and HPASMCs proliferation. Phosphorylation of PDGF and FGF receptors was augmented both 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.

Endothelial-to-mesenchymal transition in anticancer therapy and normal tissue damage

“…Nintedanib is a tyrosine kinase inhibitor that targets platelet-derived growth factor (PDGF) and the fibroblast growth factor receptor, and reduces vascular remodeling-related neointimal lesions and the medial wall thickness of pulmonary arteries. Moreover, Twist expression and related EndMT were reduced by treatment with nintedanib 28 .…”

“…Recently, several drugs in clinical testing have been reported to inhibit EndMT in various animal disease models (Table 1). These drugs inhibit EndMT by targeting various signaling molecules, such as DPP-4 25,96 , Smad 97 , TGF-β [97][98][99] , AMPK 100 , and other proteins 28,[101][102][103][104][105][106] .…”

“…Nintedanib, which has been approved for treating pulmonary fibrosis, showed anti-vascular remodeling effects in pulmonary hypertension 28 . Macitentan was approved for treating pulmonary fibrosis and inhibited TGF-β-and ET-1-mediated EndMT in ECs isolated from patients with systemic sclerosis 98 .…”

Endothelial-to-Mesenchymal Transition in Cancer

“…Inhibiting kinase signaling engaged by recently identified EndMT-inducing factors such as PDGF or HGF ( Huang et al, 2016 ; Liu T. et al, 2018 ) would be of interest. For example, Nintedanib, a tyrosine kinase inhibitor of PDGF, FGF, and VEGF, has been shown to ameliorate pulmonary hypertension by blocking EndMT ( Tsutsumi et al, 2019 ) and inhibitors of the HGF receptor c-Met (e.g., carbozantinib) are at present intensively explored in Ewing sarcoma and osteosarcoma clinical trials ( Italiano et al, 2020 ).…”

Early progression of pulmonary hypertension in the monocrotaline model in males is associated with increased lung permeability

“…Patients with PH die due to the right heart failure. However, the main problem stems from vascular wall cells' proliferation, which includes endothelial [4][5][6], smooth muscle cells [7,8], and fibroblasts [9,10]. There are several animal models available to study pulmonary hypertension, including the well-established monocrotaline (MCT) [11,12] and Su5416/hypoxia (SU/Hx) [13,14] models.…”