Severe asthma is associated with a remodeling of the pulmonary arteries in horses

AbstractPulmonary hypertension and cor pulmonale are complications of severe equine asthma, as a consequence of pulmonary hypoxic vasoconstriction. However, as pulmonary hypertension is only partially reversible by oxygen administration, other etiological factors are likely involved. In human chronic obstructive pulmonary disease, pulmonary artery remodeling contributes to the development of pulmonary hypertension. In rodent models, pulmonary vascular remodeling is present as a consequence of allergic airway inflammation. The present study investigated the presence of remodeling of the pulmonary arteries in severe equine asthma, its distribution throughout the lungs, and its reversibility following long-term antigen avoidance strategies and inhaled corticosteroid administration. Using histomorphometry, the total wall area of pulmonary arteries from different regions of the lung of asthmatic horses and controls was measured. The smooth muscle mass of pulmonary arteries was also estimated on lung sections stained for α-smooth muscle actin. Reversibility of vascular changes in asthmatic horses was assessed after 1 year of antigen avoidance alone or treatment with inhaled fluticasone. Pulmonary arteries showed increased wall area in apical and caudodorsal lung regions of asthmatic horses in both exacerbation and remission. The pulmonary arteries smooth muscle mass was similarly increased. Both treatments reversed the increase in wall area. However, normalization of the vascular smooth muscle mass was observed only after treatment with antigen avoidance, but not with fluticasone. In conclusion, severe equine asthma is associated with remodeling of the pulmonary arteries consisting in an increased smooth muscle mass. The resulting narrowing of the artery lumen could enhance hypoxic vasoconstriction, contributing to pulmonary hypertension. Vascular smooth muscle mass normalization is better achieved by antigen avoidance than with inhaled corticosteroids.

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Chronic hypoxia augments depolarization-induced Ca2+ sensitization in pulmonary vascular smooth muscle through superoxide-dependent stimulation of RhoA

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00276.2009 ◽

2010 ◽

Vol 298 (2) ◽

pp. L232-L242 ◽

Cited By ~ 52

Author(s):

Brad R. S. Broughton ◽

Nikki L. Jernigan ◽

Charles E. Norton ◽

Benjimen R. Walker ◽

Thomas C. Resta

Keyword(s):

Pulmonary Hypertension ◽

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Chronic Hypoxia ◽

Pulmonary Arteries ◽

Rho Kinase ◽

Membrane Depolarization ◽

Dependent Manner ◽

Rock Inhibitor ◽

Rhoa Activation

Rho kinase (ROCK)-dependent vasoconstriction has been implicated as a major factor in chronic hypoxia (CH)-induced pulmonary hypertension. This component of pulmonary hypertension is associated with arterial myogenicity and increased vasoreactivity to receptor-mediated agonists and depolarizing stimuli resulting from ROCK-dependent myofilament Ca2+ sensitization. On the basis of separate lines of evidence that CH increases pulmonary arterial superoxide (O2−) generation and that O2− stimulates RhoA/ROCK signaling in vascular smooth muscle (VSM), we hypothesized that depolarization-induced O2− generation mediates enhanced RhoA-dependent Ca2+ sensitization in pulmonary VSM following CH. To test this hypothesis, we determined effects of the ROCK inhibitor HA-1077 and the O2−-specific spin trap tiron on vasoconstrictor reactivity to depolarizing concentrations of KCl in isolated lungs and Ca2+-permeabilized, pressurized small pulmonary arteries from control and CH (4 wk at 0.5 atm) rats. Using the same vessel preparation, we examined effects of CH on KCl-dependent VSM membrane depolarization and O2− generation using sharp electrodes and the fluorescent indicator dihydroethidium, respectively. Finally, using a RhoA-GTP pull-down assay, we investigated the contribution of O2− to depolarization-induced RhoA activation. We found that CH augmented KCl-dependent vasoconstriction through a Ca2+ sensitization mechanism that was inhibited by HA-1077 and tiron. Furthermore, CH caused VSM membrane depolarization that persisted with increasing concentrations of KCl, enhanced KCl-induced O2− generation, and augmented depolarization-dependent RhoA activation in a O2−-dependent manner. These findings reveal a novel mechanistic link between VSM membrane depolarization, O2− generation, and RhoA activation that mediates enhanced myofilament Ca2+ sensitization and pulmonary vasoconstriction following CH.

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Comparative physiology of hypoxic pulmonary hypertension: historical clues from brisket disease

Journal of Applied Physiology ◽

10.1152/japplphysiol.01017.2004 ◽

2005 ◽

Vol 98 (3) ◽

pp. 1092-1100 ◽

Cited By ~ 63

Author(s):

Jann Rhodes

Keyword(s):

Pulmonary Hypertension ◽

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Chronic Hypoxia ◽

Splice Variants ◽

Pulmonary Arteries ◽

High Mountain ◽

Hypoxic Pulmonary Hypertension ◽

And Gender ◽

Medial Hypertrophy

Some of the most valuable contributions to science have come about serendipitously, and, in 1913, when George Glover and Issac Newsom were commissioned by Colorado cattle ranchers to study high mountain disease, there was no way to anticipate the tremendous impact they would have on the study of high-altitude cardiopulmonary physiology. It was through the study of this agricultural malady that the correlation between chronic hypoxia, pulmonary hypertension, medial hypertrophy of the small pulmonary arteries, and right ventricular (RV) hypertrophy was recognized. The amount of vascular smooth muscle comprising the medial layer of pulmonary arteries varies significantly across species and can be used to predict the magnitude of pulmonary hypertension and RV hypertrophy elicited in response to chronic hypoxia. Within species, age and gender both significantly influence the severity of chronic hypoxic pulmonary hypertension and RV hypertrophy. However, despite all that we now know about hypoxic pulmonary hypertension, the specific mechanism(s) that differentiate the hypo- from the hyperresponder have yet to be elucidated. Adventitial fibroblast differentiation, circulating vascular progenitor cells, the presence or absence of specific vascular smooth muscle phenotypes, the upregulation or downregulation of vasoactive mediators, splice variants of oxygen-sensitive transcription factors, upregulation of growth factors, Ca2+ sensitization, and/or the Rho/Rho-kinases signaling cascade could all potentially play a role in determining the extent of the vascular response to hypoxia within a species. Understanding the mechanisms that determine why some people, as well as some animals, exhibit a marked susceptibility to hypoxia is an important endeavor with far-reaching implications.

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

International Journal of Molecular Sciences ◽

10.3390/ijms22094980 ◽

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.

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Perspectives on endothelial-to-mesenchymal transition: potential contribution to vascular remodeling in chronic pulmonary hypertension

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00378.2006 ◽

2007 ◽

Vol 293 (1) ◽

pp. L1-L8 ◽

Cited By ~ 202

Author(s):

Enrique Arciniegas ◽

Maria G. Frid ◽

Ivor S. Douglas ◽

Kurt R. Stenmark

Keyword(s):

Pulmonary Hypertension ◽

Smooth Muscle ◽

Vascular Remodeling ◽

Serine Proteases ◽

Structural Changes ◽

Transforming Growth Factor ◽

Pulmonary Arteries ◽

Potential Contribution ◽

Mesenchymal Transition ◽

Endothelial Mesenchymal Transition

All forms of pulmonary hypertension are characterized by structural changes in pulmonary arteries. Increased numbers of cells expressing α-smooth muscle (α-SM) actin is a nearly universal finding in the remodeled artery. Traditionally, it was assumed that resident smooth muscle cells were the exclusive source of these newly appearing α-SM actin-expressing cells. However, rapidly emerging experimental evidence suggests other, alternative cellular sources of these cells. One possibility is that endothelial cells can transition into mesenchymal cells expressing α-SM actin and that this process contributes to the accumulation of SM-like cells in vascular pathologies. We review the evidence that endothelial-mesenchymal transition is an important contributor to cardiac and vascular development as well as to pathophysiological vascular remodeling. Recent work has provided evidence for the role of transforming growth factor-β, Wnt, and Notch signaling in this process. The potential roles of matrix metalloproteinases and serine proteases are also discussed. Importantly, endothelial-mesenchymal transition may be reversible. Thus insights into the mechanisms controlling endothelial-mesenchymal transition are relevant to vascular remodeling and are important as we consider new therapies aimed at reversing pulmonary vascular remodeling.

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Abstract MP19: Smooth Muscle Cell Cytochrome B5 Reductase 3 Causes Heart Failure With Reduced Ejection Fraction Under Hypoxic Stress

Hypertension ◽

10.1161/hyp.76.suppl_1.mp19 ◽

2020 ◽

Vol 76 (Suppl_1) ◽

Author(s):

Brittany G Durgin ◽

Adam C Straub ◽

Katherine C Wood ◽

Scott A Hahn

Keyword(s):

Heart Failure ◽

Pulmonary Hypertension ◽

Smooth Muscle ◽

Ejection Fraction ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Cytochrome B5 ◽

Muscle Cells ◽

Right Heart

Pulmonary hypertension causes increased pulmonary vascular resistance and right heart failure. Nitric oxide (NO) binds to its receptor soluble guanylyl cyclase (sGC) within vascular smooth muscle cells in its reduced heme (Fe 2+ ) form to increase intracellular cGMP production, activate protein kinase G signaling, and induce vessel relaxation. In pulmonary hypertension, endothelial damage leading to decreased NO bioavailability combined with oxidation of the sGC heme (Fe 3+ ) in vascular smooth muscle cells rendering it NO-insensitive results in vasonstriction. Notably, we have previously shown that cytochrome b5 reductase 3 (CYB5R3) in vascular smooth muscle cells is an sGC reductase (Fe 3+ to Fe 2+ ) that maintains NO-dependent vasodilation in vascular disease. We therefore hypothesized that CYB5R3 confers protection in pulmonary hypertension. To test this, we subjected smooth muscle cell-specific CYB5R3 knockout mice (SMC CYB5R3 KO) to 21 days of continuous hypoxia (10% O 2 ) and assessed vascular and cardiac function. We found that SMC CYB5R3 KO led to enhanced cardiac hypertrophy when compared to wild-type (WT) controls (n=8/ group). Specifically, SMC CYB5R3 KO mice had a larger right ventricle per tibia size, left ventricle mass, and Fulton index compared to WT (n=8/ group). Moreover, SMC CYB5R3 KO mice had a significantly impaired ejection fraction and fractional shortening, and increased left ventricular posterior wall pressure (n=3-5/group). No differences in right heart function or overall cardiac fibrosis were observed between groups (n=3-5/group). With respect to vascular function, hypoxic pulmonary arteries from SMC CYB5R3 KO mice also had a blunted response to sodium nitroprusside induced NO-dependent vasodilation though no difference in sGC activator BAY 58-2667 induced NO-independent vasodilation was observed as compared to WT (n=8-11/ group). No differences in pulmonary arterial sGC levels or medial area were observed between groups (n=6-7). Combined, these data implicate that loss of SMC CYB5R3 exacerbates cardiomyocyte hypertrophy and reduces cardiac function independent of pulmonary pressure differences.

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Interaction between PGI2 and ET-1 pathways in vascular smooth muscle from Group-III pulmonary hypertension patients

Prostaglandins & Other Lipid Mediators ◽

10.1016/j.prostaglandins.2019.106388 ◽

2020 ◽

Vol 146 ◽

pp. 106388

Author(s):

Gulsev Ozen ◽

Chabha Benyahia ◽

Yasmine Amgoud ◽

Jigisha Patel ◽

Heba Abdelazeem ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Group Iii

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Upregulation of ET-1 and its receptors and remodeling in small pulmonary veins under hypoxic conditions

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.2001.280.6.l1104 ◽

2001 ◽

Vol 280 (6) ◽

pp. L1104-L1114 ◽

Cited By ~ 30

Author(s):

Hideki Takahashi ◽

Sanae Soma ◽

Masashi Muramatsu ◽

Masahiko Oka ◽

Yoshinosuke Fukuchi

Keyword(s):

Pulmonary Hypertension ◽

Smooth Muscle ◽

Vascular Remodeling ◽

Smooth Muscle Actin ◽

Pulmonary Veins ◽

Pulmonary Arteries ◽

Immunohistochemical Method ◽

Muscle Actin ◽

Converting Enzyme ◽

Hypoxic Conditions

Pulmonary veins show greater sensitivity to endothelin (ET)-1-induced vasoconstriction than pulmonary arteries, and remodeling was observed in pulmonary veins under hypoxic conditions. We examined, using an immunohistochemical method, the expression of Big ET-1, ET-converting enzyme (ECE), and ETA and ETB receptors in rat pulmonary veins under normoxic and hypoxic conditions. In control rats, Big ET-1 and ECE were coexpressed in the intima and media of the pulmonary veins, with an even distribution along the axial pathway. ETA and ETB receptors were expressed in the pulmonary veins, with a predominant distribution in the proximal segments. The expression of Big ET-1 was more abundant in the pulmonary veins than in the pulmonary arteries. After exposure to hypoxia for 7 or 14 days, the expression of Big ET-1, ECE, and ET receptors increased in small pulmonary veins. Increases in the medial thickness, wall thickness, and immunoreactivity for α-smooth muscle actin were also observed in the small pulmonary veins under hypoxic conditions. The upregulation of ET-1 and ET receptors in the small pulmonary veins is associated with vascular remodeling, which may lead to the development of hypoxic pulmonary hypertension.

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