ReviewAdaptation and Remodelling of the Pulmonary Circulation in Pulmonary Hypertension
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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2022, Biomedicine and PharmacotherapyCitation Excerpt :The vascular endothelium plays an important role in regulating vascular function. Endothelial injury or dysfunction can lead to a shift in the vasoconstriction and proliferation, which in turn leads to PH [163]. The eNOS is a calcium-dependent protease that maintains vascular function and is a hallmark of endothelial functional integrity.
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2021, Cellular SignallingCitation Excerpt :In the present study, administration of chelerythrine, an inhibitor of PKC, inhibited platelet-induced proliferation of PASMCs mediated by LOX-1. It has been documented that Stat3, as a key downstream transcription factor for PKC, promotes the expression of anti-apoptotic protein genes such as Pim-1, nuclear factor of activated T cells, matrix metalloproteinases and survivin, after phosphorylated Stat3 into the nucleus [28], resulting in the proliferation and phenotype transformation of VSMCs [52,53]. Stat3 activation has been shown to be increased in hypoxia-treated PASMCs and in PAs of monocrotaline-induced PAH rats and PAH patients [54–56].
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