scholarly journals Progenitor/Stem Cells in Vascular Remodeling during Pulmonary Arterial Hypertension

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1338
Author(s):  
France Dierick ◽  
Julien Solinc ◽  
Juliette Bignard ◽  
Florent Soubrier ◽  
Sophie Nadaud
Keyword(s):  
Stem Cells ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Vascular Lesions ◽  
Circulating Endothelial Progenitor Cells ◽  
Vascular Proliferation ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is characterized by an important occlusive vascular remodeling with the production of new endothelial cells, smooth muscle cells, myofibroblasts, and fibroblasts. Identifying the cellular processes leading to vascular proliferation and dysfunction is a major goal in order to decipher the mechanisms leading to PAH development. In addition to in situ proliferation of vascular cells, studies from the past 20 years have unveiled the role of circulating and resident vascular in pulmonary vascular remodeling. This review aims at summarizing the current knowledge on the different progenitor and stem cells that have been shown to participate in pulmonary vascular lesions and on the pathways regulating their recruitment during PAH. Finally, this review also addresses the therapeutic potential of circulating endothelial progenitor cells and mesenchymal stem cells.

scholarly journals The cancer theory of pulmonary arterial hypertension

2017 ◽  
Vol 7 (2) ◽  
pp. 285-299 ◽  
Author(s):  
Olivier Boucherat ◽  
Geraldine Vitry ◽  
Isabelle Trinh ◽  
Roxane Paulin ◽  
Steeve Provencher ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Therapeutic Potential ◽  
Antineoplastic Drugs ◽  
Resistant Clone ◽  
Pulmonary Arterial ◽  
Pulmonary Artery Smooth Muscle

Pulmonary arterial hypertension (PAH) remains a mysterious killer that, like cancer, is characterized by tremendous complexity. PAH development occurs under sustained and persistent environmental stress, such as inflammation, shear stress, pseudo-hypoxia, and more. After inducing an initial death of the endothelial cells, these environmental stresses contribute with time to the development of hyper-proliferative and apoptotic resistant clone of cells including pulmonary artery smooth muscle cells, fibroblasts, and even pulmonary artery endothelial cells allowing vascular remodeling and PAH development. Molecularly, these cells exhibit many features common to cancer cells offering the opportunity to exploit therapeutic strategies used in cancer to treat PAH. In this review, we outline the signaling pathways and mechanisms described in cancer that drive PAH cells’ survival and proliferation and discuss the therapeutic potential of antineoplastic drugs in PAH.

scholarly journals Inhibition of Anaplerosis Attenuated Vascular Proliferation in Pulmonary Arterial Hypertension

2020 ◽  
Vol 9 (2) ◽  
pp. 443
Author(s):  
Mathews Valuparampil Varghese ◽  
Joel James ◽  
Cody A Eccles ◽  
Maki Niihori ◽  
Olga Rafikova ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Systolic Pressure ◽  
Akt Signaling ◽  
Metabolic Reprogramming ◽  
Glycolytic Flux ◽  
Vascular Cells ◽  
Vascular Proliferation ◽  
Pulmonary Arterial

Vascular remodeling is considered a key event in the pathogenesis of pulmonary arterial hypertension (PAH). However, mechanisms of gaining the proliferative phenotype by pulmonary vascular cells are still unresolved. Due to well-established pyruvate dehydrogenase (PDH) deficiency in PAH pathogenesis, we hypothesized that the activation of another branch of pyruvate metabolism, anaplerosis, via pyruvate carboxylase (PC) could be a key contributor to the metabolic reprogramming of the vasculature. In sugen/hypoxic PAH rats, vascular proliferation was found to be accompanied by increased activation of Akt signaling, which upregulated membrane Glut4 translocation and caused upregulation of hexokinase and pyruvate kinase-2, and an overall increase in the glycolytic flux. Decreased PDH activity and upregulation of PC shuttled more pyruvate to oxaloacetate. This results in the anaplerotic reprogramming of lung vascular cells and their subsequent proliferation. Treatment of sugen/hypoxia rats with the PC inhibitor, phenylacetic acid 20 mg/kg, starting after one week from disease induction, significantly attenuated right ventricular systolic pressure, Fulton index, and pulmonary vascular cell proliferation. PC inhibition reduced the glycolytic shift by attenuating Akt-signaling, glycolysis, and restored mitochondrial pyruvate oxidation. Our findings suggest that targeting PC mediated anaplerosis is a potential therapeutic intervention for the resolution of vascular remodeling in PAH.

The role of disturbed blood flow in the development of pulmonary arterial hypertension: lessons from preclinical animal models

2013 ◽  
Vol 305 (1) ◽  
pp. L1-L14 ◽  
Author(s):  
Michael G. Dickinson ◽  
Beatrijs Bartelds ◽  
Marinus A. J. Borgdorff ◽  
Rolf M. F. Berger
Keyword(s):  
Blood Flow ◽  
Pulmonary Arterial Hypertension ◽  
Animal Models ◽  
Arterial Hypertension ◽  
Human Disease ◽  
Vascular Remodeling ◽  
Pulmonary Blood Flow ◽  
Current Knowledge ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a progressive pulmonary vasoproliferative disorder characterized by the development of unique neointimal lesions, including concentric laminar intima fibrosis and plexiform lesions. Although the histomorphology of neointimal lesions is well described, the pathogenesis of PAH and neointimal development is largely unknown. After three decades of PAH pathobiology research the focus has shifted from vasoconstriction towards a mechanism of cancer-like angioproliferation. In this concept the role of disturbed blood flow is seen as an important trigger in the development of vascular remodeling. For instance, in PAH associated with congenital heart disease, increased pulmonary blood flow (i.e., systemic-to-pulmonary shunt) is an essential trigger for the occurrence of neointimal lesions and PAH development. Still, questions remain about the exact role of these blood flow characteristics in disease progression. PAH animal models are important for obtaining insight in new pathobiological processes and therapeutical targets. However, as for any preclinical model the pathophysiological mechanism and clinical course has to be comparable to the human disease that it mimics. This means that animal models mimicking human PAH ideally are characterized by: a hit recognized in human disease (e.g., altered pulmonary blood flow), specific vascular remodeling resembling human neointimal lesions, and disease progression that leads to right ventriclular dysfunction and death. A review that underlines the current knowledge of PAH due to disturbed flow is still lacking. In this review we will summarize the current knowledge obtained from PAH animal models associated with disturbed pulmonary blood flow and address questions for future treatment strategies for PAH.

scholarly journals Schistosome-Associated Pulmonary Arterial Hypertension: A Review Emphasizing Pathogenesis

2021 ◽  
Vol 8 ◽  
Author(s):  
Teresa Cristina Abreu Ferrari ◽  
Ana Cristina Lopes Albricker ◽  
Ina Morais Gonçalves ◽  
Cláudia Maria Vilas Freire
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Transforming Growth Factor ◽  
Current Knowledge ◽  
Vascular Lesions ◽  
Heart Catheterization ◽  
Right Heart ◽  
Phosphodiesterase Type 5 Inhibitors ◽  
Difficult Condition ◽  
Pulmonary Arterial

Schistosomiasis, especially due to Schistosoma mansoni, is a well-recognized cause of pulmonary arterial hypertension (PAH). The high prevalence of this helminthiasis makes schistosome-related PAH (Sch-PAH) one of the most common causes of this disorder worldwide. The pathogenic mechanisms underlying Sch-PAH remain largely unknown. Available evidence suggests that schistosome eggs reach the lung via portocaval shunts formed as a consequence of portal hypertension due to hepatosplenic schistosomiasis. Once deposited into the lungs, the eggs elicit an immune response resulting in periovular granuloma formation. Immune mediators drive transforming growth factor-β (TGF-β) release, which gives rise to pulmonary vascular inflammation with subsequent remodeling and development of angiomatoid and plexiform lesions. These mechanisms elicited by the eggs seem to become autonomous and the vascular lesions progress independently of the antigen. Portopulmonary hypertension, which pathogenesis is still uncertain, may also play a role in the genesis of Sch-PAH. Recently, there have been substantial advances in the diagnosis and treatment of PAH, but it remains a difficult condition to recognize and manage, and patients still die prematurely from right-heart failure. Echocardiography is used for screening, and the formal diagnosis requires right-heart catheterization. The experience in treating Sch-PAH is largely limited to the phosphodiesterase type 5 inhibitors, with evidence suggesting that these vasodilators improve symptoms and may also improve survival. Considering the great deal of uncertainty about Sch-PAH pathogenesis, course, and treatment, the aim of this review is to summarize current knowledge on this condition emphasizing its pathogenesis.

Model Characterization of Pulmonary Arterial Hypertension: Analysis of Lung Pathology with Respect to Human Disease

2020 ◽  
Author(s):  
◽  
Eptisam lambu
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Human Disease ◽  
Vascular Remodeling ◽  
Vascular Wall ◽  
Lung Pathology ◽  
Pulmonary Arterial ◽  
Lung Pathogenesis ◽  
Arterial Endothelial Cells

Pulmonary arterial hypertension (PAH) is a rare multifactorial disease characterized by abnormal high blood pressure in the pulmonary artery, or increased pulmonary vascular resistance (PVR), caused by obstruction in the small arteries of the lung. Increased PVR is also thought to be caused by abnormal vascular remodeling, due to thickening of the pulmonary vascular wall resulting from significant hypertrophy of pulmonary arterial smooth-muscle cells (PASMCs) and increased proliferation/impaired apoptosis of pulmonary arterial endothelial cells (PAECs). Herein, we investigated the mechanisms and explored molecular pathways mediating the lung pathogenesis in two PAH rat models: Monocrotaline (MCT) and Sugen5416/Hypoxia (SuHx). We analyzed these disease models to determine where the vasculature shows the most severe PAH pathology and which model best recapitulates the human disease. We investigated the role vascular remodeling, hypoxia, cell proliferation, apoptosis, DNA damage and inflammation play in the pathogenesis of PAH. Neither model recapitulated all features of the human disease, however each model presented with some of the pathology seen in PAH patients.

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