Abstract
Galectin-3 (Gal-3) is highly expressed in fibrotic tissue related to diverse etiologies. endothelial-to-mesenchymal transition (EndoMT), A less well studied phenomenon serves as a critical process in pulmonary vascular remodeling associated with the development of pulmonary arterial hypertension (PAH). EndoMT is hypothesized to contribute to the over-proliferation of αSMA positive cells. We aim to investigate the potential role of Gal-3 in regulating EndoMT in PAH. We observed an upregulation in both Gal-3 and αSMA expression in the monocrotaline (MCT) and Hypoxia PAH model, accompanied with intimal thickening. For more profound vascular remodeling and endothelial layer lesion in former model, we employed Gal-3 knockdown and overexpression lentivirus methodology to the MCT rats to determine the mechanisms underlying abnormal endothelial cell transition in PAH. PAH was evaluated according to right ventricular systolic pressure, right heart hypertrophy and pulmonary artery remodeling. A reduction in Gal-3 was protective against the development of PAH, while Gal-3 upregulation aggravated pulmonary vascular occlusion. In addition, Gal-3 deficiency suppressed pulmonary vascular cell proliferation and macrophage infiltration. Finally, we revealed that in endothelial cells treated with tumor necrosis factor α and hypoxia (representing an in vitro model of PAH), inhibition of Gal-3 by siRNA was able to abolish the associated upregulation of αSMA. These observations suggesting Gal-3 serves as a critical mediator in PAH by regulating EndoMT. Inhibition of Gal-3 may represent a novel therapeutic target for PAH treatment.
Highlights
Pulmonary arterial hypertension (PAH) is a chronic and progressive disease leading to increased pulmonary vascular resistance, right ventricular failure and is eventually fatal [1]
Endothelial cells exposed to chronic hypoxic stressors and inflammatory factors can undergo endothelial to mesenchymal transition (EndoMT), a process which may contribute to the accumulation of smooth muscle-like cells in vascular pathologies
SD rats fed in normoxia and saline injection were taken as control group in Figure 1A, Single thin layer of ECs expressing von Willebrand factor (vWF) at EC to EC junctions immediately adjacent to smooth muscle cells, αsmooth muscle actin (αSMA) and vWF were increased in PAH model compared with control group, and PAH model vessel ECs layer dissociated, some of lumen cells was co-express of vWF and αSMA, accompanied part of endothelial cells migrate into inner layer of the vessel
Summary
Pulmonary arterial hypertension (PAH) is a chronic and progressive disease leading to increased pulmonary vascular resistance, right ventricular failure and is eventually fatal [1]. Remodeling of pulmonary vessels is determined by vascular cells phenotype changes including myofibroblasts, smooth muscle cells and endothelial cells excessive proliferation and apoptosis resistance, IS S N: 2152-5250. Galectin-3 mediates EndoMT in PAH especially associated with an increased number of αsmooth muscle actin (αSMA) expresses cells [3], which lead to medial thickening and obliteration of arterioles. There is an increasing evidence to suggest that endothelial cells [4,5,6,7] have the ability to transition into mesenchymal cells and co-express endothelial markers and αSMA. Endothelial cells exposed to chronic hypoxic stressors and inflammatory factors can undergo endothelial to mesenchymal transition (EndoMT), a process which may contribute to the accumulation of smooth muscle-like cells in vascular pathologies. Gal-3 mediates the inflammatory and fibrotic responses involved in liver[9]
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