Microstructural Changes in Collagen and Elastin and Their Impact on the Mechanics of the Pulmonary Artery in Hypertension

2011 ◽  
Author(s):  
Steven Lammers ◽  
Tosin Feyintola ◽  
Kendall Hunter ◽  
Emily Gibson ◽  
Tim Lei ◽  
...  
Keyword(s):  
Pulmonary Artery ◽  
Vascular Remodeling ◽  
Pulmonary Arteries ◽  
Right Heart Failure ◽  
Collagen Fibers ◽  
Tissue Mechanics ◽  
Microstructural Changes ◽  
Pulmonary Hemodynamic ◽  
Ideal System ◽  
Arterial Tissue

In pulmonary arteries (PA), mechanical function is largely driven by the underlying microstructure of the structural proteins collagen and elastin, which reside within the extracellular matrix (ECM) of the arterial tissue. It has long been established that much of the mechanical non-linearity associated with arterial tissue is the result of collagen mechanics. Arterial collagen is arranged within the vascular wall as tortuous fibrils with a bulk fiber orientation of roughly helical configuration. When arterial tissue is deformed, these collagen fibers become straightened in the direction of applied load. At some critical deformation, termed the transition stretch (λTrans), collagen fibers begin to carry load, thus significantly altering material stiffness. This in turn gives rise to the non-linear force-stretch (F-λ) response typical of these tissues, Figure 1. We have recently found that λTrans is significantly reduced in the hypoxia-induced pulmonary hypertensive (PH) rat model. We therefore propose that this model constitutes an ideal system to study the effect of collagen microstructure on the mechanics of arterial tissues in response to PH vascular remodeling. We hypothesize that quantitative characterization of collagen microstructure will predict pulmonary artery (PA) λTrans within this model system. By directly relating collagen microstructural changes to bulk tissue mechanics in response to PH-induced vascular remodeling we can better understand how changes in collagen structure impact pulmonary hemodynamic capacitance, a major component of cardiac load and contributing factor to right heart failure.

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

2021 ◽  
Vol 22 (9) ◽  
pp. 4980
Author(s):  
Inés Roger ◽  
Javier Milara ◽  
Paula Montero ◽  
Julio Cortijo
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Vascular Remodeling ◽  
Pulmonary Arteries ◽  
Clinical Manifestations ◽  
Different Types ◽  
Artery Remodeling ◽  
Stat Pathway ◽  
Pulmonary Artery Remodeling

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.

Understanding the Molecular Origins of Pulmonary Hypertension: Role of MicroRNAs

2012 ◽  
Vol 11 (3) ◽  
pp. 132-132
Author(s):  
Sebastien Bonnet
Keyword(s):  
Pulmonary Artery ◽  
Vascular Remodeling ◽  
Premature Death ◽  
Right Heart Failure ◽  
Pulmonary Vasculature ◽  
Inflammatory Processes ◽  
Pulmonary Arterial ◽  
Pulmonary Artery Smooth Muscle ◽  
Pulmonary Artery Endothelial Cell

Pulmonary arterial hypertension (PAH) is a disease of the pulmonary vasculature, defined by an elevated pulmonary vascular resistance, leading to right heart failure and premature death. The cause remains unknown and available treatments are limited. PAH is characterized by enhanced pulmonary artery smooth muscle cell (PASMC) and pulmonary artery endothelial cell (PAEC) proliferation and suppressed apoptosis within the pulmonary artery wall. It has been shown that this phenotype is associated with mitochondrial hyperpolarization and enhanced glycolysis over glucose oxidation (Warburg effect), which are sustained over time by the activation of the transcription factors HIF-1 and NFAT. Nonetheless, the mechanisms accounting for these abnormalities remain unknown. A common feature to all vascular remodeling processes is that in early stages of the disease, a significant increase in oxidative stress and inflammatory processes are observed, causing irreversible DNA damage and cell death.

scholarly journals Chronic Thromboembolic Pulmonary Hypertension

2018 ◽  
Vol 35 (02) ◽  
pp. 136-142 ◽  
Author(s):  
G. Pretorius ◽  
Stuart Jamieson
Keyword(s):  
Heart Failure ◽  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Pulmonary Arteries ◽  
Chronic Thromboembolic Pulmonary Hypertension ◽  
Right Heart Failure ◽  
Scar Tissue ◽  
Right Heart ◽  
Fibrotic Scar ◽  
Thromboembolic Pulmonary Hypertension

AbstractChronic thromboembolic pulmonary hypertension occurs when acute thromboemboli fail to dissolve completely. The resulting fibrotic scar tissue within the pulmonary arteries is obstructive and eventually leads to right heart failure. Medical therapy for this condition is supportive, but surgery with pulmonary artery endarterectomy is curative, and carries a low mortality at experienced centers.

Involvement of nitric oxide and nitrosothiols in relaxation of pulmonary arteries to peroxynitrite

1994 ◽  
Vol 266 (5) ◽  
pp. H2108-H2113 ◽  
Author(s):  
M. Wu ◽  
K. A. Pritchard ◽  
P. M. Kaminski ◽  
R. P. Fayngersh ◽  
T. H. Hintze ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Artery ◽  
Vascular Tissue ◽  
Soluble Guanylate Cyclase ◽  
Pulmonary Arteries ◽  
Arterial Tissue ◽  
Pulmonary Arterial ◽  
Pulmonary Arterial Smooth Muscle ◽  
Ly 83583

Peroxynitrite (ONOO-) is an inflammatory cell-derived oxidant, formed by the reaction of superoxide anion (O2-) with nitric oxide (NO), which was recently reported to relax vascular tissues. In the present study, the potential role of NO in the mechanism of relaxation in isolated bovine endothelium-denuded pulmonary arterial smooth muscle rings to ONOO- was evaluated. Potassium-preconstricted pulmonary arterial rings rapidly relaxed for a prolonged period of time on exposure to ONOO- (0.01-0.1 mM). The relaxation after 1 min of exposure to ONOO- (0.1 mM) was reduced 49 and 87%, respectively, by inhibitors of the stimulation of soluble guanylate cyclase, methylene blue, and LY-83583. In contrast, a scavenger of hydroxyl radicals, dimethyl sulfoxide, did not alter this response. Decomposed 0.1 mM ONOO- (which is primarily nitrite) and 0.1 mM nitrite caused a relaxation of pulmonary artery, which slowly developed over 15 min. Small quantities of NO were detected by chemiluminescence quantification methods when ONOO- was added to buffer. Exposure of pulmonary arterial tissue or buffer containing glutathione (GSH) to ONOO- caused a time-dependent increase in the observed generation of NO, whereas decomposed ONOO- produced 10% of the NO generated by ONOO- on incubation with pulmonary arterial tissue. Treatment with diethyl maleate, an agent that depletes tissue GSH, reduced both the relaxation and the formation of NO detected from pulmonary artery on exposure to ONOO-. GSH solutions treated with ONOO- appear to have generated a nitrosothiol-like vascular relaxant compound. Thus ONOO- appears to relax vascular tissue, in part, by nitrosylating tissue GSH (or other thiols), which subsequently releases NO over prolonged time periods.

scholarly journals MicroRNA-137 Inhibited Hypoxia-Induced Proliferation of Pulmonary Artery Smooth Muscle Cells by Targeting Calpain-2

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Xiao-Yue Ge ◽  
Tian-Tian Zhu ◽  
Mao-Zhong Yao ◽  
Hong Liu ◽  
Qian Wu ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Smooth Muscle Cells ◽  
Vascular Remodeling ◽  
Pulmonary Arteries ◽  
Muscle Cells ◽  
Sprague Dawley ◽  
Pulmonary Vascular Remodeling ◽  
Calpain 2 ◽  
Pulmonary Artery Smooth Muscle

The proliferation of pulmonary artery smooth muscle cells (PASMCs) is an important cause of pulmonary vascular remodeling in pulmonary hypertension (PH). It has been reported that miR-137 inhibits the proliferation of tumor cells. However, whether miR-137 is involved in PH remains unclear. In this study, male Sprague-Dawley rats were subjected to 10% O2 for 3 weeks to establish PH, and rat primary PASMCs were treated with hypoxia (3% O2) for 48 h to induce cell proliferation. The effect of miR-137 on PASMC proliferation and calpain-2 expression was assessed by transfecting miR-137 mimic and inhibitor. The effect of calpain-2 on PASMC proliferation was assessed by transfecting calpain-2 siRNA. The present study found for the first time that miR-137 was downregulated in pulmonary arteries of hypoxic PH rats and in hypoxia-treated PASMCs. miR-137 mimic inhibited hypoxia-induced PASMC proliferation and upregulation of calpain-2 expression in PASMCs. Furthermore, miR-137 inhibitor induced the proliferation of PASMCs under normoxia, and knockdown of calpain-2 mRNA by siRNA significantly inhibited hypoxia-induced proliferation of PASMCs. Our study demonstrated that hypoxia-induced downregulation of miR-137 expression promoted the proliferation of PASMCs by targeting calpain-2, thereby potentially resulting in pulmonary vascular remodeling in hypoxic PH.

Short-term exercise training increases ACh-induced relaxation and eNOS protein in porcine pulmonary arteries

2001 ◽  
Vol 90 (3) ◽  
pp. 1102-1110 ◽  
Author(s):  
Lynelle R. Johnson ◽  
James W. E. Rush ◽  
James R. Turk ◽  
Elmer M. Price ◽  
M. Harold Laughlin
Keyword(s):  
Pulmonary Artery ◽  
Pulmonary Arteries ◽  
Fold Increase ◽  
Immunoblot Analysis ◽  
Short Term ◽  
Miniature Swine ◽  
Lung Lobe ◽  
Arterial Tissue ◽  
Enos Protein

We tested the hypothesis that short-term exercise (STEx) training and the associated increase in pulmonary blood flow during bouts of exercise cause enhanced endothelium-dependent vasorelaxation in porcine pulmonary arteries and increased expression of endothelial cell nitric oxide synthase (eNOS) and superoxide dismutase-1 (SOD-1) protein. Mature, female Yucatan miniature swine exercised 1 h twice daily on a motorized treadmill for 1 wk (STEx group, n = 7); control pigs (Sed, n = 6) were kept in pens. Pulmonary arteries were isolated from the left caudal lung lobe, and vasomotor responses were determined in vitro. Arterial tissue from the distal portion of this pulmonary artery was processed for immunoblot analysis. Maximal endothelium-dependent (ACh-stimulated) relaxation was greater in STEx (71 ± 5%) than in Sed (44 ± 6%) arteries ( P < 0.05), and endothelium-independent (sodium nitroprusside-mediated) responses did not differ. Sensitivity to ACh was not altered by STEx training. Immunoblot analysis indicated a 3.9-fold increase in eNOS protein in pulmonary artery tissue from STEx pigs ( P < 0.05) with no change in SOD-1 or glyceraldehyde-3-phosphate dehydrogenase protein levels. We conclude that STEx training enhances ACh-stimulated vasorelaxation in pulmonary arterial tissue and that this adaptation is associated with increased expression of eNOS protein.

Abstract 17034: The AKT/AMPK/FOXO3 Axis in Pulmonary Arterial Hypertension

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Yann Grobs ◽  
Charlotte romanet ◽  
Valerie Nadeau ◽  
Junichi Omura ◽  
Mark Orcholski ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Pulmonary Arteries ◽  
Right Heart Failure ◽  
Metabolic Reprogramming ◽  
Nuclear Exclusion ◽  
Pulmonary Arterial

Like cancer, pulmonary arterial hypertension (PAH) is characterized by exaggerated proliferation and resistance to apoptosis related to metabolic alterations (Warburg effect) of pulmonary smooth muscle cells (PASMCs). These anomalies result in a progressive narrowing of the pulmonary arteries, increasing pulmonary resistance and leading to right heart failure and premature death. In cancer cells, unphosphorylated and nuclear FOXO3 has been extensively studied as a crucial protein that functions as a tumor suppressor by regulating expression of genes involved in apoptosis and cell cycle arrest. These functions combined with other FOXO3 attributes, including its key role in communicating mitochondrial-nuclear signals, make the FOXO3 a suitable candidate for controlling the cancer-like phenotype of PAH-PASMCs. Interestingly, AKT and AMPK known to be implicated in PAH exert antagonistic effects on FOXO3; AKT promoting its nuclear exclusion while AMPK favors its nuclear and mitochondrial accumulation. The thus made the hypothesis that FOXO3’s nuclear exclusion (secondary to AKT/AMPK imbalance) promotes metabolic reprogramming towards glycolysis leading to enhanced proliferation/resistance to apoptosis of PAH-PASMCs and vascular remodeling. Using Western blot and immunofluorescence in isolated PASMCs from both PAH and control patients (n=10), we found that nuclear and mitochondrial exclusion of FOXO3 due to its phosphorylation is a feature of PAH-PASMCs. In vitro, we demonstrated that nuclear localization of FOXO3 using an adenovirus expressing a constitutively active, non-phosphorylable form of FOXO3 or trifluoperazine (TFP) resulted in reduced PAH-PASMC proliferation (Ki67 labeling, p<0,0005) and resistance to apoptosis (Annexin V assay, p<0,05). These effects were accompanied by increased expression of P27 and SOD2 and diminished expression of Survivin (p<0,05). In vivo, we showed that FOXO3 activation using TPF improved established PAH in the monocrotaline rats (reduced RVSP and increased Sv and CO, by right catheterization, p<0,01, n=29) without any sign of toxicity. We showed that FOXO3 is implicated in pulmonary vascular remodeling. Pharmacological activation of FOXO3 may represent a novel avenue to improve PAH.

scholarly journals Extranodal Rosai–Dorfman Disease Presenting as a Mediastinal Mass with Pulmonary Artery Invasion

2018 ◽  
Vol 2018 ◽  
pp. 1-5
Author(s):  
Andrew R. Orr ◽  
Daniel Lefler ◽  
C. Deshpande ◽  
Pallavi Kumar
Keyword(s):  
Pulmonary Artery ◽  
Mediastinal Mass ◽  
Case Reports ◽  
Pulmonary Arteries ◽  
Right Heart Failure ◽  
Cervical Lymph Nodes ◽  
Aged Woman ◽  
Rosai Dorfman Disease ◽  
Middle Aged Woman ◽  
Extranodal Manifestations

Rosai–Dorfman disease (RDD) is a rare, nonmalignant disorder of histiocyte proliferation typically involving the cervical lymph nodes. However, a subset of patients with RDD will display extranodal manifestations that are highly variable in presentation, more challenging to diagnose, and less likely to spontaneously regress compared to nodal disease. While case reports of extranodal involvement in nearly every organ system exist, documented instances of mediastinal and pulmonary artery involvement are particularly rare. This study describes the case of a middle-aged woman presenting with new onset right heart failure who was found to have extranodal RDD in the form of a large mediastinal mass with invasion and occlusion of the main pulmonary arteries.

Vascular remodeling and ET-1 expression in rat strains with different responses to chronic hypoxia

2000 ◽  
Vol 278 (5) ◽  
pp. L981-L987 ◽  
Author(s):  
J. I. Aguirre ◽  
N. W. Morrell ◽  
L. Long ◽  
P. Clift ◽  
P. D. Upton ◽  
...  
Keyword(s):  
Pulmonary Artery ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Pulmonary Arteries ◽  
Bronchial Epithelium ◽  
Northern Analysis ◽  
Pulmonary Vascular Remodeling ◽  
Fischer 344 ◽  
Wky Rats ◽  
Wistar Kyoto

Chronic hypoxia leads to a greater degree of pulmonary hypertension in the Wistar-Kyoto (WKY) rat than in the Fischer 344 (F-344) rat. We questioned whether this difference is associated with baseline differences in pulmonary artery anatomy, a greater degree of hypoxia-induced pulmonary vascular remodeling in the WKY rat, and/or differences in expression of endothelin (ET)-1. Male F-344 and WKY rats were maintained in normoxia or normobaric hypoxia for 21 days. Morphometry revealed that baseline pulmonary artery anatomy was similar in the two strains. However, during chronic hypoxia, the WKY rats developed a greater degree of muscularization of small pulmonary arteries. Baseline plasma and lung immunoreactive ET-1 levels were similar in the WKY and F-344 rats and increased significantly during hypoxia in the WKY rats. Northern analysis demonstrated increased lung preproET-1 mRNA during hypoxia in both strains, with a greater increase in WKY rats. Immunostaining demonstrated increased ET-1 in bronchial epithelium and peripheral pulmonary arteries during hypoxia, although to a greater degree in the WKY rats. We conclude that the WKY strain demonstrates increased susceptibility to hypoxia-induced pulmonary vascular remodeling compared with the F-344 strain and that increased lung and circulating ET-1 levels during hypoxia may partly explain this difference.

scholarly journals A Notch3-Marked Subpopulation of Vascular Smooth Muscle Cells Is the Cell of Origin for Occlusive Pulmonary Vascular Lesions

Circulation ◽  
2020 ◽  
Vol 142 (16) ◽  
pp. 1545-1561
Author(s):  
Lea C. Steffes ◽  
Alexis A. Froistad ◽  
Adam Andruska ◽  
Mario Boehm ◽  
Madeleine McGlynn ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Smooth Muscle Cells ◽  
Vascular Remodeling ◽  
Pulmonary Arteries ◽  
Muscle Cells ◽  
Neointima Formation ◽  
Cell Of Origin ◽  
Medial Thickening

Background: Pulmonary arterial hypertension (PAH) is a fatal disease characterized by profound vascular remodeling in which pulmonary arteries narrow because of medial thickening and occlusion by neointimal lesions, resulting in elevated pulmonary vascular resistance and right heart failure. Therapies targeting the neointima would represent a significant advance in PAH treatment; however, our understanding of the cellular events driving neointima formation, and the molecular pathways that control them, remains limited. Methods: We comprehensively map the stepwise remodeling of pulmonary arteries in a robust, chronic inflammatory mouse model of pulmonary hypertension. This model demonstrates pathological features of the human disease, including increased right ventricular pressures, medial thickening, neointimal lesion formation, elastin breakdown, increased anastomosis within the bronchial circulation, and perivascular inflammation. Using genetic lineage tracing, clonal analysis, multiplexed in situ hybridization, immunostaining, deep confocal imaging, and staged pharmacological inhibition, we define the cell behaviors underlying each stage of vascular remodeling and identify a pathway required for neointima formation. Results: Neointima arises from smooth muscle cells (SMCs) and not endothelium. Medial SMCs proliferate broadly to thicken the media, after which a small number of SMCs are selected to establish the neointima. These neointimal founder cells subsequently undergoing massive clonal expansion to form occlusive neointimal lesions. The normal pulmonary artery SMC population is heterogeneous, and we identify a Notch3-marked minority subset of SMCs as the major neointimal cell of origin. Notch signaling is specifically required for the selection of neointimal founder cells, and Notch inhibition significantly improves pulmonary artery pressure in animals with pulmonary hypertension. Conclusions: This work describes the first nongenetically driven murine model of pulmonary hypertension (PH) that generates robust and diffuse occlusive neointimal lesions across the pulmonary vascular bed and does so in a stereotyped timeframe. We uncover distinct cellular and molecular mechanisms underlying medial thickening and neointima formation and highlight novel transcriptional, behavioral, and pathogenic heterogeneity within pulmonary artery SMCs. In this model, inflammation is sufficient to generate characteristic vascular pathologies and physiological measures of human PAH. We hope that identifying the molecular cues regulating each stage of vascular remodeling will open new avenues for therapeutic advancements in the treatment of PAH.

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