Investigation of the Role of Endothelial TGF-β2 in the Development of Atherosclerosis

The transforming growth factor-beta (TGF-β) family comprises three isoforms, namely TGF-β1, TGF-β2, and TGF-β3. They play significant roles in inflammation, tissue repair and fibrosis. The involvement of these isoforms in the development of atherosclerosis is fascinatingly complex and context- or cell type-dependent. They can exert either a protective or detrimental effect. The results from existing literature provide clear indication that different isoforms are likely to exert distinct effects. Further investigation of the intricate functions of TGF-β isoforms in the vasculature will undoubtedly provide insights into new therapeutic approaches for the prevention and treatment of atherosclerotic vascular diseases. The endothelial cells lining in the interior of vessels are directly exposed to physical and chemical stimuli. This exposure allows us to comprehend how endothelial cell dysfunction represents the most important initiator of atherosclerosis. In our preliminary study, we conducted a reanalysis of our single-cell RNA-seq and bulk RNA-seq data, which yielded an intriguing observation. Our findings indicate that TGF-β signaling and its associated endothelial-to-mesenchymal transition are significantly enriched in endothelial cells of ApoE-/- mice. Furthermore, we observed elevated TGF-β2 expression in endothelial layers of plaque lesions in human arteries and mouse aortas relative to plaque-free arteries. This suggests that TGF-β2 may be a key player in the initiation and progression of atherosclerosis. Nevertheless, there is still so much to be discovered regarding the precise function of endothelial TGF-β2 activation in conjunction with other proinflammatory cytokines in atherogenesis. The principal objective of this project is to investigate molecular mechanisms through which TGF-β2 activation plays a critical role in endothelial dysfunction and inflammatory responses at the onset and progression of atherosclerosis. To this end, the project will pursue the following three objectives, which are inter-connected and of great interest: (1) To investigate the role of endothelial TGF-β2 in the pathogenesis of atherosclerosis. (2) To investigate the mechanisms underlying TGF-β2-induced inflammatory responses in endothelial cells (3) To investigate the mechanisms by which shear stress regulates the expression of endothelial TGF-β2 and to screen anti-atherosclerotic TGF-β2 inhibitors As a logical extension of our previous research on atherosclerosis, the new findings from this project will provide invaluable insights into the potential development of TGF-β2- targeted therapeutic strategies against atherosclerotic vascular disease, which could have a significant impact on public health.