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. 2018 Nov 8;5:163. doi: 10.3389/fcvm.2018.00163

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Copyright © 2018 Chellan, Sutton and Hofmann Bowman.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Schematic overview of phenotypic switch of contractile SMCs to osteoblast-like SMC by uptake of enzyme modified LDL in the medial layer and neo-intima in blood vessels. 1a: entry of circulating monocytes and transformation to macrophage foam cells provides enzymatic and inflammatory input for various modifications of native low density lipoprotein (LDL). 1b: Modification of LDL to oxidized LDL (oxLDL) by Phospholipase A2 (sPLA2), Lipoxygenase or Myeloperoxidase. oxLDL is readily taken by macrophages. 2a: Cholesterol esterase together with proteases (plasmin, metalloproteinases (MMPs) or cathepsin) generate non-oxidized enzymatic modified LDL (ELDL). ELDL is taken up by smooth muscle cells via macropinocytosis. 2b: uptake of ELDL activates cell signaling pathways (MAPK, ERK, NFkB) and downregulates mRNA for ectonucleotide pyrophosphatase/phosphodiesterase (ENPP-1), matrix gla protein (MGP) and upregulates mRNA for bone morphogenic protein 2 (BMP2), dentin matrix protein 1 (DMP1), osteopontin (SPP1), and osterix (SP7).