Endothelial Dysfunction in Pulmonary Hypertension: Cause or Consequence?

Kurakula, Kondababu; Smolders, Valérie F. E. D.; Tura-Ceide, Olga; Jukema, J. Wouter; Quax, Paul H.A.; Goumans, Marie–José

doi:10.3390/biomedicines9010057

Cited by 76 publications

(64 citation statements)

References 192 publications

(133 reference statements)

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“…It is now recognized that perivascular inflammation is a common contributing factor in almost all forms of PH [ 103 , 104 , 105 , 106 ] because inflammatory cell infiltrates comprising T- and B-lymphocytes and macrophages have been identified. Upon endothelial cell injury, HPAECs become dysfunctional and alter their secretion of cytokines and other factors that regulate coagulation, thrombosis, and vascular tone [ 107 ]. However, the exact mechanisms by which inflammation might facilitate the progression of PH are still under investigation.…”

Section: Jak/stat Pathway and Cellular And Molecular Dysregulation In Pulmonary Hypertensionmentioning

confidence: 99%

The Role of JAK/STAT Molecular Pathway in Vascular Remodeling Associated with Pulmonary Hypertension

Roger

Milara

Montero

et al. 2021

IJMS

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Pulmonary hypertension is defined as a group of diseases characterized by a progressive increase in pulmonary vascular resistance (PVR), which leads to right ventricular failure and premature death. There are multiple clinical manifestations that can be grouped into five different types. Pulmonary artery remodeling is a common feature in pulmonary hypertension (PH) characterized by endothelial dysfunction and smooth muscle pulmonary artery cell proliferation. The current treatments for PH are limited to vasodilatory agents that do not stop the progression of the disease. Therefore, there is a need for new agents that inhibit pulmonary artery remodeling targeting the main genetic, molecular, and cellular processes involved in PH. Chronic inflammation contributes to pulmonary artery remodeling and PH, among other vascular disorders, and many inflammatory mediators signal through the JAK/STAT pathway. Recent evidence indicates that the JAK/STAT pathway is overactivated in the pulmonary arteries of patients with PH of different types. In addition, different profibrotic cytokines such as IL-6, IL-13, and IL-11 and growth factors such as PDGF, VEGF, and TGFβ1 are activators of the JAK/STAT pathway and inducers of pulmonary remodeling, thus participating in the development of PH. The understanding of the participation and modulation of the JAK/STAT pathway in PH could be an attractive strategy for developing future treatments. There have been no studies to date focused on the JAK/STAT pathway and PH. In this review, we focus on the analysis of the expression and distribution of different JAK/STAT isoforms in the pulmonary arteries of patients with different types of PH. Furthermore, molecular canonical and noncanonical JAK/STAT pathway transactivation will be discussed in the context of vascular remodeling and PH. The consequences of JAK/STAT activation for endothelial cells and pulmonary artery smooth muscle cells’ proliferation, migration, senescence, and transformation into mesenchymal/myofibroblast cells will be described and discussed, together with different promising drugs targeting the JAK/STAT pathway in vitro and in vivo.

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Section: Jak/stat Pathway and Cellular And Molecular Dysregulation In Pulmonary Hypertensionmentioning

confidence: 99%

The Role of JAK/STAT Molecular Pathway in Vascular Remodeling Associated with Pulmonary Hypertension

Roger

Milara

Montero

et al. 2021

IJMS

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“…Amabile et al reported an increased number of circulating EMVs in a mixed group of patients with different pulmonary hypertension aetiologies, including PAH and chronic pulmonary disease–related pulmonary hypertension, which correlated to disease severity [ 14 , 25 ]. Additionally, in PAH, EMVs have been considered key modulators in inflammatory and coagulation PAH-associated processes [ 26 , 27 , 28 ].…”

Section: Discussionmentioning

confidence: 99%

Circulating Cell Biomarkers in Pulmonary Arterial Hypertension: Relationship with Clinical Heterogeneity and Therapeutic Response

Tura-Ceide

Blanco

García-Lucio

et al. 2021

Cells

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Background: Endothelial dysfunction is central to PAH. In this study, we simultaneously analysed circulating levels of endothelial microvesicles (EMVs) and progenitor cells (PCs) in PAH and in controls, as biomarkers of pulmonary endothelial integrity and evaluated differences among PAH subtypes and as a response to treatment. Methods: Forty-seven controls and 144 patients with PAH (52 idiopathic, 9 heritable, 31 associated with systemic sclerosis, 15 associated with other connective tissue diseases, 20 associated with HIV and 17 associated with portal hypertension) were evaluated. Forty-four patients with scleroderma and 22 with HIV infection, but without PAH, were also studied. Circulating levels of EMVs, total (CD31+CD42b−) and activated (CD31+CD42b−CD62E+), as well as circulating PCs (CD34+CD133+CD45low) were measured by flow cytometry and the EMVs/PCs ratio was computed. In treatment-naïve patients, measurements were repeated after 3 months of PAH therapy. Results: Patients with PAH showed higher numbers of EMVs and a lower percentage of PCs, compared with healthy controls. The EMV/PC ratio was increased in PAH patients, and in patients with SSc or HIV without PAH. After starting PAH therapy, individual changes in EMVs and PCs were variable, without significant differences being observed as a group. Conclusion: PAH patients present disturbed vascular homeostasis, reflected in changes in circulating EMV and PC levels, which are not restored with PAH targeted therapy. Combined measurement of circulating EMVs and PCs could be foreseen as a potential biomarker of endothelial dysfunction in PAH.

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“…PAH is a life-threatening disorder consisting in a progressive increase in pulmonary vascular resistance, which can ultimately lead to right heart failure and patient’s death. PAH is triggered by endothelial injury, which paves the way to the emergence of apoptosis-resistant and hyperproliferative endothelial cells that display impaired release of vasorelaxing mediators and contribute to the formation of occlusive intimal lesions [ 306 , 307 ]. In addition, pulmonary-resident ECFCs could support the proliferative angiopathic process in PAH [ 308 ].…”

Section: Therapeutic Applications and Pathological Implications Of Ros-induced Endothelial Ca 2+ Signalsmentioning

confidence: 99%

Reactive Oxygen Species and Endothelial Ca2+ Signaling: Brothers in Arms or Partners in Crime?

Negri¹,

Faris²,

Moccia³

2021

IJMS

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An increase in intracellular Ca2+ concentration ([Ca2+]i) controls virtually all endothelial cell functions and is, therefore, crucial to maintain cardiovascular homeostasis. An aberrant elevation in endothelial can indeed lead to severe cardiovascular disorders. Likewise, moderate amounts of reactive oxygen species (ROS) induce intracellular Ca2+ signals to regulate vascular functions, while excessive ROS production may exploit dysregulated Ca2+ dynamics to induce endothelial injury. Herein, we survey how ROS induce endothelial Ca2+ signals to regulate vascular functions and, vice versa, how aberrant ROS generation may exploit the Ca2+ handling machinery to promote endothelial dysfunction. ROS elicit endothelial Ca2+ signals by regulating inositol-1,4,5-trisphosphate receptors, sarco-endoplasmic reticulum Ca2+-ATPase 2B, two-pore channels, store-operated Ca2+ entry (SOCE), and multiple isoforms of transient receptor potential (TRP) channels. ROS-induced endothelial Ca2+ signals regulate endothelial permeability, angiogenesis, and generation of vasorelaxing mediators and can be exploited to induce therapeutic angiogenesis, rescue neurovascular coupling, and induce cancer regression. However, an increase in endothelial [Ca2+]i induced by aberrant ROS formation may result in endothelial dysfunction, inflammatory diseases, metabolic disorders, and pulmonary artery hypertension. This information could pave the way to design alternative treatments to interfere with the life-threatening interconnection between endothelial ROS and Ca2+ signaling under multiple pathological conditions.

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Endothelial Dysfunction in Pulmonary Hypertension: Cause or Consequence?

Cited by 76 publications

References 192 publications

The Role of JAK/STAT Molecular Pathway in Vascular Remodeling Associated with Pulmonary Hypertension

The Role of JAK/STAT Molecular Pathway in Vascular Remodeling Associated with Pulmonary Hypertension

Circulating Cell Biomarkers in Pulmonary Arterial Hypertension: Relationship with Clinical Heterogeneity and Therapeutic Response

Reactive Oxygen Species and Endothelial Ca2+ Signaling: Brothers in Arms or Partners in Crime?

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