Calcification is an independent predictor of atherosclerosis-related cardiovascular events. Microcalcification is linked to inflamed, unstable lesions, in comparison to the fibrotic stable plaque phenotype generally associated with advanced calcification. This paradox relates to recognition that calcification presents in a wide spectrum of manifestations that differentially impact plaque’s fate. Macrophages, the main inflammatory cells in atherosclerotic plaque, have a multifaceted role in disease progression. They crucially control the mineralization process, from microcalcification to the osteoid metaplasia of bone-like tissue. It is a bilateral interaction that weighs heavily on the overall plaque fate but remains rather unexplored. This review highlights current knowledge about macrophage phenotypic changes in relation to and interaction with the calcifying environment. On the one hand, macrophage-led inflammation kickstarts microcalcification through a multitude of interlinked mechanisms, which in turn stimulates phenotypic changes in vascular cell types to drive microcalcification. Macrophages may also modulate the expression/activity of calcification inhibitors and inducers, or eliminate hydroxyapatite nucleation points. Contrarily, direct exposure of macrophages to an early calcifying milieu impacts macrophage phenotype, with repercussions for plaque progression and/or stability. Macrophages surrounding macrocalcification deposits show a more reparative phenotype, modulating extracellular matrix, and expressing osteoclast genes. This phenotypic shift favours gradual displacement of the pro-inflammatory hubs; the lipid necrotic core, by macrocalcification. Parallels to bone metabolism may explain many of these changes to macrophage phenotype, with advanced calcification able to show homeostatic osteoid metaplasia. As the targeted treatment of vascular calcification developing in atherosclerosis is thus far severely lacking, it is crucial to better understand its mechanisms of development.

中文翻译：

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双面Janus：巨噬细胞在动脉粥样硬化钙化中的双重作用

钙化是动脉粥样硬化相关心血管事件的独立预测因子。与通常与晚期钙化相关的纤维化稳定斑块表型相比，微钙化与发炎的、不稳定的病变有关。这个悖论与认识到钙化存在于广泛的表现形式有关，这些表现形式对斑块的命运有不同的影响。巨噬细胞是动脉粥样硬化斑块中的主要炎症细胞，在疾病进展中具有多方面的作用。它们至关重要地控制矿化过程，从微钙化到骨样组织的类骨质化生。这是一种双边互动，对斑块的整体命运产生了很大影响，但仍未得到探索。这篇综述强调了目前关于巨噬细胞表型变化与钙化环境相关和相互作用的知识。一方面，巨噬细胞引发的炎症通过多种相互关联的机制启动微钙化，进而刺激血管细胞类型的表型变化以驱动微钙化。巨噬细胞还可以调节钙化抑制剂和诱导剂的表达/活性，或消除羟基磷灰石成核点。相反，巨噬细胞直接暴露于早期钙化环境会影响巨噬细胞表型，从而影响斑块进展和/或稳定性。巨钙化沉积物周围的巨噬细胞表现出更具修复性的表型，可调节细胞外基质并表达破骨细胞基因。这种表型转变有利于促炎中心的逐渐置换；脂质坏死核心，通过大钙化。与骨代谢的相似之处可以解释巨噬细胞表型的许多变化，晚期钙化能够显示出稳态骨样化生。由于迄今为止严重缺乏对动脉粥样硬化中发生的血管钙化的靶向治疗，因此更好地了解其发展机制至关重要。