Vaillancourt Mylène, Ruffenach Grégoire, Meloche Jolyane, Bonnet Sébastien
Pulmonary Hypertension Research Group of The Quebec Heart And Lung Institute Research Centre, Québec City, Québec, Canada.
Pulmonary Hypertension Research Group of The Quebec Heart And Lung Institute Research Centre, Québec City, Québec, Canada.
Can J Cardiol. 2015 Apr;31(4):407-15. doi: 10.1016/j.cjca.2014.10.023. Epub 2014 Oct 23.
Pulmonary arterial hypertension (PAH) is characterized by remodelling of pulmonary arteries caused by a proliferation/apoptosis imbalance within the vascular wall. This pathological phenotype seems to be triggered by different environmental stress and injury events such as increased inflammation, DNA damage, and epigenetic deregulation. It appears that one of the first hit to occur is endothelial cells (ECs) injury and apoptosis, which leads to paracrine signalling to other ECs, pulmonary artery smooth muscle cells (PASMCs), and fibroblasts. These signals promote a phenotypic change of surviving ECs by disturbing different signalling pathways leading to sustained vasoconstriction, proproliferative and antiapoptotic phenotype, deregulated angiogenesis, and formation of plexiform lesions. EC signalling also recruits proinflammatory cells, leading to pulmonary infiltration of lymphocytes, macrophages, and dendritic cells, sustaining the inflammatory environment and autoimmune response. Finally, EC signalling promotes proliferative and antiapoptotic PAH-PASMC phenotypes, which acquire migratory capacities, resulting in increased vascular wall thickness and muscularization of small pulmonary arterioles. Adaptation and remodelling of pulmonary circulation also involves epigenetic components, such as microRNA deregulation, DNA methylation, and histone modification. This review will focus on the different cellular and epigenetic aspects including EC stress response, molecular mechanisms contributing to PAH-PASMC and PAEC proliferation and resistance to apoptosis, as well as epigenetic control involved in adaptation and remodelling of the pulmonary circulation in PAH.
肺动脉高压（PAH）的特征是血管壁内增殖/凋亡失衡导致肺动脉重塑。这种病理表型似乎由不同的环境应激和损伤事件触发，如炎症增加、DNA损伤和表观遗传失调。似乎最早发生的打击之一是内皮细胞（ECs）损伤和凋亡，这会导致向其他ECs、肺动脉平滑肌细胞（PASMCs）和成纤维细胞的旁分泌信号传导。这些信号通过干扰不同的信号通路促进存活ECs的表型变化，导致持续的血管收缩、促增殖和抗凋亡表型、血管生成失调以及丛状病变的形成。EC信号传导还招募促炎细胞，导致淋巴细胞、巨噬细胞和树突状细胞的肺浸润，维持炎症环境和自身免疫反应。最后，EC信号传导促进增殖性和抗凋亡性PAH-PASMC表型，这些表型获得迁移能力，导致血管壁厚度增加和小肺动脉肌化。肺循环的适应和重塑还涉及表观遗传成分，如微小RNA失调、DNA甲基化和组蛋白修饰。本综述将聚焦于不同的细胞和表观遗传方面，包括EC应激反应、导致PAH-PASMC和PAEC增殖及抗凋亡的分子机制，以及PAH中肺循环适应和重塑所涉及的表观遗传调控。
