Abstract
Atherosclerosis, is a chronic inflammatory disease, characterized by the narrowing of the arteries resulting from the formation of intimal plaques in the wall of arteries. Yet the molecular mechanisms responsible for maintaining the development and progression of atherosclerotic lesions have not been fully defined. In this study, we show that TGF-β activates the endothelial-to-mesenchymal transition (EndMT) in cultured human aortic endothelial cells (HAECs) and this transition is dependent on the key executor of the Wnt signaling pathway in vitro. This study presents the first evidence describing the mechanistic details of the TGF-β-induced EndMT signaling pathway in HAECs by documenting the cellular transition to the mesenchymal phenotype including the expression of mesenchymal markers α-SMA and PDGFRα, and the loss of endothelial markers including VE-cadherin and CD31. Furthermore, a short hairpin RNA (shRNA) screening revealed that Wnt2 signaling is required for TGF-β-mediated EndMT of HAECs. Also, we found that LDLR−/− mice fed on a high-fat western-type diet (21% fat, 0.2% cholesterol) expressed high levels of Wnt2 protein in atherosclerotic lesions, confirming that this signaling pathway is involved in atherosclerosis in vivo. These findings suggest that Wnt2 may contribute to atherosclerotic plaque development and this study will render Wnt2 as a potential target for therapeutic intervention aiming at controlling atherosclerosis.
Highlights
Atherosclerosis is characterized by thickening of the arterial wall plaque resulting in narrowing of the vessel and restricted blood flow
whole cell lysate (WCL) from tumor growth factor (TGF)-β2-treated cells were analyzed by Western blot (WB) to detect the expression of the endothelial cell markers, cadherin Vascular endothelialcadherin (VE)-cadherin and CD31, and mesenchymal markers, platelet-derived growth factor receptor α (PDGFRα) and α-smooth muscle actin (α-SMA)
Since atherogenesis is a chronic process, we exposed the human aortic endothelial cells (HAECs) cells to TGF-β2 for a longer time point (5 days) as shown in Supplementary Figure 1, we observed that the endothelial-to-mesenchymal transition (EndMT) status is still maintained, which is confirmed by the expression of EndMT markers
Summary
Atherosclerosis is characterized by thickening of the arterial wall plaque resulting in narrowing of the vessel and restricted blood flow. Atherosclerotic plaques arise from the accumulation of immune cells, smooth muscle cells (SMC), fibroblasts, lipids and extracellular matrix (ECM) in the arterial wall. These atherosclerotic changes are the major cause of heart attacks, peripheral vascular disease and other illnesses that collectively account for the majority of deaths and morbidity in the world [1, 2]. The atherosclerotic risk factors including high blood pressure, smoking and obesity result in disturbing the blood flow. This suggests the importance of haemodynamic forces in the initiation of the disease [3].
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