Review
Adaptation and Remodelling of the Pulmonary Circulation in Pulmonary Hypertension

https://doi.org/10.1016/j.cjca.2014.10.023Get rights and content

Abstract

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.

Résumé

L’hypertension artérielle pulmonaire (HTAP) est caractérisée par le remodelage des artères pulmonaires causé par un déséquilibre entre la prolifération et l’apoptose de la paroi vasculaire. Ce phénotype pathologique semble être déclenché par divers stress environnementaux et événements lésionnels tels que l’augmentation de l’inflammation, les dommages à l’ADN et la dérégulation épigénétique. Il semble que l'un des éléments déclencheurs soit le dommage aux cellules endothéliales (CE), induisant l'apoptose et conduisant à la signalisation paracrine à d’autres CE, cellules musculaires lisses des artères pulmonaires (CMLAP) et fibroblastes. Ces signaux favorisent un changement phénotypique CE survivantes en perturbant les différentes voies de signalisation conduisant à un maintien de la vasoconstriction, au phénotype proprolifératif et antiapoptique, à la dérégulation de l’angiogenèse et à la formation de lésions plexiformes. La signalisation des CE recrute également des cellules pro-inflammatoires, conduisant à l’infiltration pulmonaire des lymphocytes, des macrophages et des cellules dendritiques, qui contribuent au maintien de l’environnement inflammatoire et de la réponse auto-immune. Finalement, la signalisation des CE favorise un phénotype prolifératif et anti-apoptotique des CMLAP-HTAP, qui acquièrent des capacités migratoires entraînant l’augmentation de l’épaisseur de la paroi vasculaire et de la muscularisation des artérioles pulmonaires. L’adaptation et le remodelage de la circulation pulmonaire impliquent également des composantes épigénétiques comme la dérégulation de micro-ARN, la méthylation de l’ADN et la modification des histones. Cette revue soulignera les différents aspects cellulaires et épigénétiques, y compris la réponse des CE au stress, les mécanismes moléculaires contribuant au phénotype prolifératif et anti-apoptotique des CMLAP- et CE-HTAP, ainsi que le contrôle épigénétique, tous impliqués dans l’adaptation et le remodelage de la circulation pulmonaire lors d’HTAP.

Section snippets

Endothelial Response to Injury

The endothelial response to injury can be divided into 2 phases: an initial/rapid response followed by a phenotypic response.7 The initial response is rapid and involves changes in levels of nitric oxide (NO), endothelin-1 (ET-1), thromboxane, and 5-hydroxytryptamine (5-HT). This will lead to initial PA endothelial cell (PAEC) apoptosis, disruption of the endothelial layer, and exposure of the subendothelium to soluble growth factors and cytokines. In the phenotypic response, apoptotic

Role of Inflammation and Autoimmunity

Accumulating evidence suggests that inflammation contributes to the vascular abnormalities observed in PAH and correlate with vascular thickening.5, 6 The inflammatory environment is mainly composed of increased inflammatory cells, cytokines, and chemokines.23

Molecular Mechanisms Contributing to PAH-PASMC and -PAEC Proliferation and Resistance to Apoptosis

As described herein, endothelial dysfunction and inflammation contribute to the development of vascular lesions in PAH. In the second half of our review, we will discuss the molecular mechanisms that trigger and maintain the PASMC and PAEC proliferation/apoptosis imbalance.40

Epigenetic Mechanisms of PH

The role for epigenetics in PAH is a fast-growing area of research.60, 61 Epigenetics is defined as all molecular mechanisms implicated in gene expression regulation at the genome level, without modification of the DNA sequence. The major epigenetic phenomena include microRNAs (miRNAs), DNA methylation, and histone modifications.

Conclusions

In conclusion, the molecular mechanisms of PAH, a disease for which there is no cure, is not yet fully understood. It is believed that the endothelial dysfunction is a key factor in triggering vasoconstriction and subsequent vascular remodelling, but PAH pathobiology is very complex and involves many components such as proproliferative and antiapoptotic PAECs and PASMCs, a proinflammatory environment, and epigenetic deregulation. All of these disorders put together lead to increased pulmonary

Funding Sources

M.V. received a Canadian Institutes of Health Research graduate scholarship and J.M. was awarded a FRQS PhD scholarship. Canada Research Chairs and Canadian Institutes of Health Research grants (CIHR grant MOP-119294) to S.B. supported this work.

Disclosures

The authors have no conflicts of interest to disclose.

Acknowledgements

Mylène Vaillancourt and Grégoire Ruffenach contributed equally to this work.

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