Acute absolute vasodilatation is associated with a lower vascular wall stiffness in pulmonary arterial hypertension

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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Iloprost for acute tests in patients with pulmonary arterial hypertension

Systemic Hypertension ◽

10.26442/sg28944 ◽

2012 ◽

Vol 9 (4) ◽

pp. 54-57

Author(s):

E A Belyatko ◽

N M Danilov ◽

Y G Matchin ◽

T V Martynyuk ◽

I E Chazova

Keyword(s):

Nitric Oxide ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Intima Media Thickness ◽

Vascular Wall ◽

Right Heart Catheterization ◽

Heart Catheterization ◽

Hemodynamic Changes ◽

Pulmonary Arterial ◽

Inner Diameter

Objective: in our study, iloprost was used as a drug for acute tests in patients with pulmonary arterial hypertension (PAH). Design and Method. We included 7 pts with pulmonary arterial hypertension (PAH): 5 females and 2 males, average age 32,0±12,0 years. All patients underwent right heart catheterization including acute tests with both nitric oxide and Iloprost. In addition to hemodynamic changes the intravascular ultrasound (IVUS) parameters were analyzed. We used parameters such as: intima-media thickness, the pulsatility index (PI), the outer and inner diameter of the vessel, the area of the vascular wall. Results. Compared with the action of nitric oxide, the degree of reduction of medium pulmonary arterial pressure (mPAP) after Iloprost was 17,2±5 and 25,37±9 mm Hg respectively, and pulmonary vascular resistance (PVR) 251,4±120 and 276±129 dynes×c×cm-5 respectively (p

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Image-based computational assessment of vascular wall mechanics and hemodynamics in pulmonary arterial hypertension patients

Journal of Biomechanics ◽

10.1016/j.jbiomech.2017.12.022 ◽

2018 ◽

Vol 68 ◽

pp. 84-92 ◽

Cited By ~ 14

Author(s):

Byron A. Zambrano ◽

Nathan A. McLean ◽

Xiaodan Zhao ◽

Ju-Le Tan ◽

Liang Zhong ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Vascular Wall ◽

Pulmonary Arterial

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The hallmarks of severe pulmonary arterial hypertension: the cancer hypothesis—ten years later

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00476.2019 ◽

2020 ◽

Vol 318 (6) ◽

pp. L1115-L1130 ◽

Cited By ~ 8

Author(s):

Carlyne D. Cool ◽

Wolfgang M. Kuebler ◽

Harm Jan Bogaard ◽

Edda Spiekerkoetter ◽

Mark R. Nicolls ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Cell Injury ◽

Vascular Endothelial Cell ◽

Treatment Strategies ◽

Vascular Wall ◽

Vascular Endothelial ◽

Proliferating Cells ◽

Bone Marrow Derived Cells ◽

Pulmonary Arterial

Severe forms of pulmonary arterial hypertension (PAH) are most frequently the consequence of a lumen-obliterating angiopathy. One pathobiological model is that the initial pulmonary vascular endothelial cell injury and apoptosis is followed by the evolution of phenotypically altered, apoptosis-resistant, proliferating cells and an inflammatory vascular immune response. Although there may be a vasoconstrictive disease component, the increased pulmonary vascular shear stress in established PAH is caused largely by the vascular wall pathology. In this review, we revisit the “quasi-malignancy concept” of severe PAH and examine to what extent the hallmarks of PAH can be compared with the hallmarks of cancer. The cancer model of severe PAH, based on the growth of abnormal vascular and bone marrow-derived cells, may enable the emergence of novel cell-based PAH treatment strategies.

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Epigenetic Targets for Oligonucleotide Therapies of Pulmonary Arterial Hypertension

International Journal of Molecular Sciences ◽

10.3390/ijms21239222 ◽

2020 ◽

Vol 21 (23) ◽

pp. 9222

Author(s):

William Gerthoffer

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Small Molecules ◽

Vascular Remodeling ◽

Arterial Wall ◽

Vascular Wall ◽

Wall Structure ◽

Wall Thickening ◽

Pulmonary Arterial

Arterial wall remodeling underlies increased pulmonary vascular resistance and right heart failure in pulmonary arterial hypertension (PAH). None of the established vasodilator drug therapies for PAH prevents or reverse established arterial wall thickening, stiffening, and hypercontractility. Therefore, new approaches are needed to achieve long-acting prevention and reversal of occlusive pulmonary vascular remodeling. Several promising new drug classes are emerging from a better understanding of pulmonary vascular gene expression programs. In this review, potential epigenetic targets for small molecules and oligonucleotides will be described. Most are in preclinical studies aimed at modifying the growth of vascular wall cells in vitro or normalizing vascular remodeling in PAH animal models. Initial success with lung-directed delivery of oligonucleotides targeting microRNAs suggests other epigenetic mechanisms might also be suitable drug targets. Those targets include DNA methylation, proteins of the chromatin remodeling machinery, and long noncoding RNAs, all of which act as epigenetic regulators of vascular wall structure and function. The progress in testing small molecules and oligonucleotide-based drugs in PAH models is summarized.

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Wave reflection correlates with pulmonary vascular wall thickening in rats with pulmonary arterial hypertension

International Journal of Cardiology ◽

10.1016/j.ijcard.2017.09.024 ◽

2017 ◽

Vol 249 ◽

pp. 396-401 ◽

Cited By ~ 3

Author(s):

Masafumi Fukumitsu ◽

Toru Kawada ◽

Shuji Shimizu ◽

Michael J. Turner ◽

Kazunori Uemura ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Wave Reflection ◽

Vascular Wall ◽

Wall Thickening ◽

Pulmonary Arterial

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Spatio-Temporal Diversity of Apoptosis Within the Vascular Wall in Pulmonary Arterial Hypertension

Circulation Research ◽

10.1161/01.res.0000204572.65400.a5 ◽

2006 ◽

Vol 98 (2) ◽

pp. 172-175 ◽

Cited By ~ 47

Author(s):

Evangelos D. Michelakis

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Vascular Wall ◽

Temporal Diversity ◽

Pulmonary Arterial ◽

Spatio Temporal

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Chronic inflammation within the vascular wall in pulmonary arterial hypertension: more than a spectator

Cardiovascular Research ◽

10.1093/cvr/cvz308 ◽

2019 ◽

Vol 116 (5) ◽

pp. 885-893 ◽

Cited By ~ 7

Author(s):

Alice Huertas ◽

Ly Tu ◽

Marc Humbert ◽

Christophe Guignabert

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Vascular Wall ◽

Direct Role ◽

Future Studies ◽

Functional Changes ◽

Persistent Inflammation ◽

Tunica Adventitia ◽

Pulmonary Arterial ◽

Tunica Intima

Abstract This review seeks to provide an update of preclinical findings and available clinical data on the chronic persistent inflammation and its direct role on the pulmonary arterial hypertension (PAH) progression. We reviewed the different mechanisms by which the inflammatory and immune pathways contribute to the structural and functional changes occurring in the three vascular compartments: the tunica intima, tunica media, and tunica adventitia. We also discussed how these inflammatory mediator changes may serve as a biomarker of the PAH progression and summarize unanswered questions and opportunities for future studies in this area.

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Patient-Specific Computational Analysis of Hemodynamics and Wall Mechanics and Their Interactions in Pulmonary Arterial Hypertension

Frontiers in Bioengineering and Biotechnology ◽

10.3389/fbioe.2020.611149 ◽

2021 ◽

Vol 8 ◽

Author(s):

Byron A. Zambrano ◽

Nathan McLean ◽

Xiaodan Zhao ◽

Ju-Le Tan ◽

Liang Zhong ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Pulmonary Arteries ◽

Patient Specific ◽

Pulmonary Vasculature ◽

Control Group ◽

Regurgitant Flow ◽

Wall Stiffness ◽

Wall Deformation ◽

Pulmonary Arterial

Vascular wall stiffness and hemodynamic parameters are potential biomechanical markers for detecting pulmonary arterial hypertension (PAH). Previous computational analyses, however, have not considered the interaction between blood flow and wall deformation. Here, we applied an established computational framework that utilizes patient-specific measurements of hemodynamics and wall deformation to analyze the coupled fluid–vessel wall interaction in the proximal pulmonary arteries (PA) of six PAH patients and five control subjects. Specifically, we quantified the linearized stiffness (E), relative area change (RAC), diastolic diameter (D), regurgitant flow, and time-averaged wall shear stress (TAWSS) of the proximal PA, as well as the total arterial resistance (Rt) and compliance (Ct) at the distal pulmonary vasculature. Results found that the average proximal PA was stiffer [median: 297 kPa, interquartile range (IQR): 202 kPa vs. median: 75 kPa, IQR: 5 kPa; P = 0.007] with a larger diameter (median: 32 mm, IQR: 5.25 mm vs. median: 25 mm, IQR: 2 mm; P = 0.015) and a reduced RAC (median: 0.22, IQR: 0.10 vs. median: 0.42, IQR: 0.04; P = 0.004) in PAH compared to our control group. Also, higher total resistance (Rt; median: 6.89 mmHg × min/l, IQR: 2.16 mmHg × min/l vs. median: 3.99 mmHg × min/l, IQR: 1.15 mmHg × min/l; P = 0.002) and lower total compliance (Ct; median: 0.13 ml/mmHg, IQR: 0.15 ml/mmHg vs. median: 0.85 ml/mmHg, IQR: 0.51 ml/mmHg; P = 0.041) were observed in the PAH group. Furthermore, lower TAWSS values were seen at the main PA arteries (MPAs) of PAH patients (median: 0.81 Pa, IQR: 0.47 Pa vs. median: 1.56 Pa, IQR: 0.89 Pa; P = 0.026) compared to controls. Correlation analysis within the PAH group found that E was directly correlated to the PA regurgitant flow (r = 0.84, P = 0.018) and inversely related to TAWSS (r = −0.72, P = 0.051). Results suggest that the estimated elastic modulus E may be closely related to PAH hemodynamic changes in pulmonary arteries.

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miR-223 reverses experimental pulmonary arterial hypertension

AJP Cell Physiology ◽

10.1152/ajpcell.00149.2015 ◽

2015 ◽

Vol 309 (6) ◽

pp. C363-C372 ◽

Cited By ~ 71

Author(s):

Jolyane Meloche ◽

Marie Le Guen ◽

François Potus ◽

Jérôme Vinck ◽

Benoit Ranchoux ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Hypoxia Inducible Factor ◽

Pulmonary Arteries ◽

Vascular Wall ◽

Loss Of Function ◽

Beneficial Effects ◽

Pulmonary Arterial ◽

Ventricle Hypertrophy ◽

Parp 1

Pulmonary arterial hypertension (PAH) is a devastating disease affecting lung vasculature. The pulmonary arteries become occluded due to increased proliferation and suppressed apoptosis of the pulmonary artery smooth muscle cells (PASMCs) within the vascular wall. It was recently shown that DNA damage could trigger this phenotype by upregulating poly(ADP-ribose)polymerase 1 (PARP-1) expression, although the exact mechanism remains unclear. In silico analyses and studies in cancer demonstrated that microRNA miR-223 targets PARP-1. We thus hypothesized that miR-223 downregulation triggers PARP-1 overexpression, as well as the proliferation/apoptosis imbalance observed in PAH. We provide evidence that miR-223 is downregulated in human PAH lungs, distal PAs, and isolated PASMCs. Furthermore, using a gain and loss of function approach, we showed that increased hypoxia-inducible factor 1α, which is observed in PAH, triggers this decrease in miR-223 expression and subsequent overexpression of PARP-1 allowing PAH-PASMC proliferation and resistance to apoptosis. Finally, we demonstrated that restoring the expression of miR-223 in lungs of rats with monocrotaline-induced PAH reversed established PAH and provided beneficial effects on vascular remodeling, pulmonary resistance, right ventricle hypertrophy, and survival. We provide evidence that miR-223 downregulation in PAH plays an important role in numerous pathways implicated in the disease and restoring its expression is able to reverse PAH.

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