The role that vascular smooth muscle cell (VSMC)-derived foam cells play as drivers of atherosclerosis has been an increasing focus of recent research interest. Toll-like receptor 4 (TLR4) has been identified as a regulator of the formation of VSMC foam cells, while vitamin D can reportedly suppress macrophage-derived foam cell development. Our aim is to investigate whether vitamin D can similarly suppress the formation of VSMC foam cells, as well as the role of TLR4 in this pathogenic context. The impact of vitamin D on VSMC-derived foam cell and atherosclerotic plaque formation was assessed, and the expression of cholesterol transport-related genes and TLR4 was assessed in ApoE-/- mice. The impact of 1,25(OH)2D3 on the ox-LDL-mediated formation of foam cells and the underlying molecular mechanisms were also examined in VSMCs cultured in vitro. Supplemental vitamin D administration resulted in a pronounced reduction in aortic atherosclerotic plaque formation and the development of SMA-α-positive foam cells. Vitamin D further suppressed TLR4, CD36 and SR-A in atherosclerotic plaque lesions while promoting ABCA1, ABCG1 and LXR-α upregulation. 1,25(OH)2D3 significantly reduced Dil-ox-LDL uptake and increased NBD-LDL efflux in VSMCs, in addition to suppressing TLR4, CD36 and SR-A expression, while upregulating ABCA1, ABCG1 and LXR-α. TLR4 knockdown impaired VSMC foam cell formation, while 1,25(OH)2D3-induced JNK activation suppressed TLR4 signaling and promoted VSMC foam cell development. Our study reveals that vitamin D can reduce VSMC foam cell formation and protect against atherosclerotic progression through the JNK-TLR4 signaling pathway.
Keywords: athrosclerosis; foam cell; toll-like receptor 4; vascular smooth muscle cells; vitamin D.