Unique wreath-like smooth muscle proliferation of the pulmonary vasculature in pulmonary veno-occlusive disease versus pulmonary arterial hypertension

Rationale: Pulmonary arterial hypertension (PAH) is a devastating disease in which oxidative stress has been proposed to mediate pathological changes to the pulmonary vasculature such as endothelial cell (EC) apoptosis, endothelial to mesenchymal transition (EndMT), vascular smooth muscle cell (VSMC) proliferation, and inflammation. Our previous study showed that cyclophilin A (CypA) was secreted from EC and VSMC in response to oxidative stress, and much of the secreted CypA was acetylated (AcK-CypA). Furthermore, CypA was increased in the plasma of patients with PAH. Objective: To evaluate the cell- s pecific role of CypA in PAH and compare the relative effects of AcK-CypA and CypA on EC apoptosis, development of an inflammatory EC phenotype and EndMT. Methods and Results: Transgenic overexpression of CypA in EC, but not SMC, caused a PAH phenotype including increased pulmonary artery pressure, α-smooth muscle actin expression in small arteries, and CD45 positive cells in the lungs. Mechanistic analysis using cultured mouse lung microvascular EC showed that CypA and AcK-CypA increased apoptosis measured by caspase 3 cleavage and TUNEL staining. MM284, a specific inhibitor of extracellular CypA, prevented EC apoptosis. In addition, CypA and AcK-CypA promoted an EC inflammatory phenotype assessed by increased VCAM1 and ICAM1 expression, phosphorylation of p65, and degradation of IkB. Furthermore, CypA and AcK-CypA promoted EndMT assayed by change in cell morphology, increased mesenchymal markers and EndMT related transcription factors. At all concentrations, AcK-CypA stimulated greater increases in apoptosis, inflammation and EndMT than CypA. Conclusions: EC-derived CypA (especially AcK-CypA) causes PAH by a presumptive mechanism involving increased EC apoptosis, inflammation and EndMT. Our results suggest that inhibiting extracellular secreted CypA is a novel therapeutic approach for PAH.

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Expression of Plateled-Derived Growth Factor Receptor β (PDGFR-β) and Epidermal GFR (EGFR) in Pulmonary Vasculature of Systemic Sclerosis-Associated Pulmonary Arterial Hypertension (SScPH)vs.Idiopathic PH (IPH) and Pulmonary Veno-Occlusive Disease (PVOD).

10.1164/ajrccm-conference.2009.179.1_meetingabstracts.a4931 ◽

2009 ◽

Author(s):

MJ Overbeek ◽

A Boonstra ◽

E Smit ◽

A Voskuyl ◽

A Vonk-Noordegraaf ◽

...

Keyword(s):

Systemic Sclerosis ◽

Growth Factor ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Growth Factor Receptor ◽

Occlusive Disease ◽

Pulmonary Vasculature ◽

Pulmonary Arterial

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Smooth Muscle Proliferation and Role of the Prostacyclin (IP) Receptor in Idiopathic Pulmonary Arterial Hypertension

American Journal of Respiratory and Critical Care Medicine ◽

10.1164/rccm.201001-0011oc ◽

2010 ◽

Vol 182 (9) ◽

pp. 1161-1170 ◽

Cited By ~ 83

Author(s):

Emilia Falcetti ◽

Susan M. Hall ◽

Peter G. Phillips ◽

Jigisha Patel ◽

Nicholas W. Morrell ◽

...

Keyword(s):

Smooth Muscle ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Idiopathic Pulmonary Arterial Hypertension ◽

Smooth Muscle Proliferation ◽

Ip Receptor ◽

Pulmonary Arterial

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Ion channels as convergence points in the pathology of pulmonary arterial hypertension

Biochemical Society Transactions ◽

10.1042/bst20210538 ◽

2021 ◽

Author(s):

Thibault R. H. Jouen-Tachoire ◽

Stephen J. Tucker ◽

Paolo Tammaro

Keyword(s):

Smooth Muscle ◽

Ion Channels ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Molecular Mechanisms ◽

Muscle Tone ◽

Pulmonary Vasculature ◽

Extrinsic Factors ◽

Pulmonary Arterial ◽

Vascular Smooth Muscle Tone

Pulmonary arterial hypertension (PAH) is a fatal disease of the cardiopulmonary system that lacks curative treatments. The main pathological event in PAH is elevated vascular resistance in the pulmonary circulation, caused by abnormal vasoconstriction and vascular remodelling. Ion channels are key determinants of vascular smooth muscle tone and homeostasis, and four PAH channelopathies (KCNK3, ABCC8, KCNA5, TRPC6) have been identified so far. However, the contribution of ion channels in other forms of PAH, which account for the majority of PAH patients, has been less well characterised. Here we reason that a variety of triggers of PAH (e.g. BMPR2 mutations, hypoxia, anorectic drugs) that impact channel function may contribute to the onset of the disease. We review the molecular mechanisms by which these ‘extrinsic’ factors converge on ion channels and provoke their dysregulation to promote the development of PAH. Ion channels of the pulmonary vasculature are therefore promising therapeutic targets because of the modulation they provide to both vasomotor tone and proliferation of arterial smooth muscle cells.

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