scholarly journals Pulmonary vessel casting in a rat model of monocrotaline-mediated pulmonary hypertension

2020 ◽  
Vol 10 (3) ◽  
pp. 204589402092212
Author(s):  
Zhongkai Zhu ◽  
Yifan Wang ◽  
Amy Long ◽  
Tianyu Feng ◽  
Maria Ocampo ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Rat Model ◽  
Vascular System ◽  
Pulmonary Arteries ◽  
Pulmonary Vasculature ◽  
Control Group ◽  
Wall Thickening ◽  
Arterial Remodeling ◽  
Pulmonary Vessel ◽  
Pulmonary Arterial

Pulmonary hypertension is a chronic vascular disease characterized by pulmonary vasoconstriction and pulmonary arterial remodeling. Pulmonary arterial remodeling is mainly due to small pulmonary arterial wall thickening and lumen occlusion. Previous studies have described intravascular changes in lung sections using histopathology, but few were able to obtain a fine detailed image of the pulmonary vascular system. In this study, we used Microfil compounds to cast the pulmonary arteries in a rat model of monocrotaline-induced pulmonary hypertension. High-quality images that enabled quantification of distal pulmonary arterial branching based on the number of vessel bifurcations/junctions were demonstrated in this model. The branch and junction counts of distal pulmonary arteries significantly decreased in the monocrotaline group compared to the control group, and this effect was inversely proportional to the mean pulmonary artery pressure observed in each group. The patterns of pulmonary vasculature and the methods for pulmonary vessel casting are presented to provide a basis for future studies of pulmonary arterial remodeling due to pulmonary hypertension and other lung diseases that involve the remodeling of vasculature.

scholarly journals Hypercapnia attenuates hypoxic pulmonary hypertension by inhibiting lung radical injury

2009 ◽  
pp. S79-S86 ◽  
Author(s):  
M Chovanec ◽  
J Novotná ◽  
J Wilhelm ◽  
V Hampl ◽  
M Vízek ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arteries ◽  
Male Rats ◽  
Pulmonary Vasculature ◽  
Hypoxic Pulmonary Hypertension ◽  
Hypoxic Injury ◽  
Arterial Blood ◽  
Hypoxic Environment ◽  
Pulmonary Arterial ◽  
The Right

Chronic lung hypoxia results in hypoxic pulmonary hypertension. Concomitant chronic hypercapnia partly inhibits the effect of hypoxia on pulmonary vasculature. Adult male rats exposed to 3 weeks hypoxia (Fi02=0.1) combined with hypercapnia (FiC02=0.04-0.05) had lower pulmonary arterial blood pressure, increased weight of the right heart ventricle, and less pronounced structural remodeling of the peripheral pulmonary arteries compared with rats exposed only to chronic hypoxia (Fi02=0.1). According to our hypothesis, hypoxic pulmonary hypertension is triggered by hypoxic injury to the walls of the peripheral pulmonary arteries. Hypercapnia inhibits release of both oxygen radicals and nitric oxide at the beginning of exposure to the hypoxic environment. The plasma concentration of nitrotyrosine, the marker of peroxynitrite activity, is lower in hypoxic rats exposed to hypercapnia than in those exposed to hypoxia alone. Hypercapnia blunts hypoxia-induced collagenolysis in the walls of prealveolar pulmonary arteries. We conclude that hypercapnia inhibits the development of hypoxic pulmonary hypertension by the inhibition of radical injury to the walls of peripheral pulmonary arteries.

scholarly journals Multiple roles of macrophage migration inhibitory factor in pulmonary hypertension

2020 ◽  
Vol 318 (1) ◽  
pp. L1-L9 ◽  
Author(s):  
Gael Jalce ◽  
Christophe Guignabert
Keyword(s):  
Pulmonary Hypertension ◽  
Migration Inhibitory Factor ◽  
Macrophage Migration Inhibitory Factor ◽  
Scientific Evidence ◽  
Pulmonary Arteries ◽  
Inhibitory Factor ◽  
Pulmonary Vasculature ◽  
Macrophage Migration ◽  
Multifactorial Diseases ◽  
Pulmonary Arterial

Pulmonary hypertension (PH) is a life-threatening condition arising from the loss and obstructive remodeling of the pulmonary arteries, leading to the sustained elevation of pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR) and subsequently right ventricular (RV) failure and death. PH encompasses a group of multifactorial diseases, such as pulmonary arterial hypertension (PAH) and chronic thromboembolic PH, for which there is no treatment that can stop or reverse the progression of remodeling of the pulmonary vasculature. The identification of new molecular targets for the development of more effective drugs is thus urgently needed. In this context, macrophage migration inhibitory factor (MIF), a pleiotropic upstream proinflammatory mediator, is emerging as a promising molecular target, as it contributes to perivascular inflammation and pulmonary arterial remodeling, two key hallmarks of PAH that are not specifically targeted by currently approved therapies. The objective of this review is to summarize the scientific evidence on the pathogenic roles of MIF and its potential as a biomarker and therapeutic target in PH/PAH.

scholarly journals Ion Channels in Pulmonary Hypertension: A Therapeutic Interest?

2018 ◽  
Vol 19 (10) ◽  
pp. 3162 ◽  
Author(s):  
Mélanie Lambert ◽  
Véronique Capuano ◽  
Andrea Olschewski ◽  
Jessica Sabourin ◽  
Chandran Nagaraj ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Ion Channels ◽  
Pulmonary Arterial Hypertension ◽  
Therapeutic Potential ◽  
Severe Disease ◽  
Pulmonary Vasculature ◽  
Pulmonary Vessel ◽  
Vessel Remodeling ◽  
Pulmonary Arterial ◽  
Arterial Tone

Pulmonary arterial hypertension (PAH) is a multifactorial and severe disease without curative therapies. PAH pathobiology involves altered pulmonary arterial tone, endothelial dysfunction, distal pulmonary vessel remodeling, and inflammation, which could all depend on ion channel activities (K+, Ca2+, Na+ and Cl−). This review focuses on ion channels in the pulmonary vasculature and discusses their pathophysiological contribution to PAH as well as their therapeutic potential in PAH.

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

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.

scholarly journals The Expression of Proteins Related to Serotonin Pathway in Pulmonary Arteries of Dogs Affected With Pulmonary Hypertension Secondary to Degenerative Mitral Valve Disease

2020 ◽  
Vol 7 ◽  
Author(s):  
Siriwan Sakarin ◽  
Sirilak Disatian Surachetpong ◽  
Anudep Rungsipipat
Keyword(s):  
Pulmonary Hypertension ◽  
Mitral Valve ◽  
Mitral Valve Disease ◽  
Tryptophan Hydroxylase ◽  
Pulmonary Arteries ◽  
Valve Disease ◽  
Control Group ◽  
Healthy Control ◽  
Pulmonary Arterial ◽  
Medial Thickening

Background: Pulmonary hypertension (PH) can cause medial thickening, a hallmark of pulmonary arterial remodeling. The serotonin (5HT) pathway has been suggested as a factor associated with PH by inducing pulmonary arterial smooth muscle cells (SMCs) proliferation, a major cause of medial thickening. This study aims to demonstrate the expression of molecules in the 5HT pathway in the pulmonary artery of dogs affected with PH secondary to degenerative mitral valve disease (DMVD) compared to DMVD and healthy control dogs.Materials and Methods: The study included lung samples from the carcasses of 19 older small-breed dogs (Control n = 5, DMVD n = 7, DMVD+PH n = 7). Lung tissue sections were performed Hematoxylin and Eosin staining for measuring the percentage of medial thickness and immunohistochemistry for evaluating the expression of proteins in the 5HT pathway including serotonin transporter (SERT), serotonin 2A receptor (5HT2A), tryptophan hydroxylase 1 (TPH1), extracellular regulated kinase 1/2 (ERK1/2), and phosphorylated ERK1/2 (pERK1/2).Results: Medial thickening of the pulmonary arteries was found in the DMVD and DMVD+PH groups compared to the control. The medial thickening of the DMVD+PH group was increased significantly compared to that in the DMVD group. Intracytoplasmic expression of proteins related to the 5HT pathway was mainly presented in the medial layer of the pulmonary arteries. The control group showed a low expression of proteins related to the 5HT pathway. An intensive expression of SERT, 5HT2A, TPH1, and ERK1/2 protein was seen in the DMVD and DMVD+PH groups. Interestingly, pERK1/2 was strongly represented only in the DMVD+PH group.Conclusions: Overexpression of proteins related to the 5HT pathway including SERT, 5HT2A, TPH1, ERK1/2, and pERK1/2 was associated with medial remodeling in dogs affected with secondary to DMVD.

scholarly journals Hypoxia-induced glucose-6-phosphate dehydrogenase overexpression and -activation in pulmonary artery smooth muscle cells: implication in pulmonary hypertension

2015 ◽  
Vol 308 (3) ◽  
pp. L287-L300 ◽  
Author(s):  
Sukrutha Chettimada ◽  
Rakhee Gupte ◽  
Dhwajbahadur Rawat ◽  
Sarah A. Gebb ◽  
Ivan F. McMurtry ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Pulmonary Arteries ◽  
Pentose Phosphate ◽  
Arterial Remodeling ◽  
Altered Glucose ◽  
Pulmonary Arterial ◽  
Pulmonary Artery Smooth Muscle ◽  
Glucose 6 Phosphate Dehydrogenase

Severe pulmonary hypertension is a debilitating disease with an alarmingly low 5-yr life expectancy. Hypoxia, one of the causes of pulmonary hypertension, elicits constriction and remodeling of the pulmonary arteries. We now know that pulmonary arterial remodeling is a consequence of hyperplasia and hypertrophy of pulmonary artery smooth muscle (PASM), endothelial, myofibroblast, and stem cells. However, our knowledge about the mechanisms that cause these cells to proliferate and hypertrophy in response to hypoxic stimuli is still incomplete, and, hence, the treatment for severe pulmonary arterial hypertension is inadequate. Here we demonstrate that the activity and expression of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway, are increased in hypoxic PASM cells and in lungs of chronic hypoxic rats. G6PD overexpression and -activation is stimulated by H2O2. Increased G6PD activity contributes to PASM cell proliferation by increasing Sp1 and hypoxia-inducible factor 1α (HIF-1α), which directs the cells to synthesize less contractile (myocardin and SM22α) and more proliferative (cyclin A and phospho-histone H3) proteins. G6PD inhibition with dehydroepiandrosterone increased myocardin expression in remodeled pulmonary arteries of moderate and severe pulmonary hypertensive rats. These observations suggest that altered glucose metabolism and G6PD overactivation play a key role in switching the PASM cells from the contractile to synthetic phenotype by increasing Sp1 and HIF-1α, which suppresses myocardin, a key cofactor that maintains smooth muscle cell in contractile state, and increasing hypoxia-induced PASM cell growth, and hence contribute to pulmonary arterial remodeling and pathogenesis of pulmonary hypertension.

BMPR-II heterozygous mice have mild pulmonary hypertension and an impaired pulmonary vascular remodeling response to prolonged hypoxia

2004 ◽  
Vol 287 (6) ◽  
pp. L1241-L1247 ◽  
Author(s):  
Hideyuki Beppu ◽  
Fumito Ichinose ◽  
Noriko Kawai ◽  
Rosemary C. Jones ◽  
Paul B. Yu ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Primary Pulmonary Hypertension ◽  
Pulmonary Arterial Pressure ◽  
Pulmonary Arteries ◽  
Pulmonary Vasculature ◽  
Wild Type ◽  
Mean Pulmonary Arterial Pressure ◽  
Pulmonary Arterial ◽  
Alveolar Capillary

Heterozygous mutations of the bone morphogenetic protein type II receptor ( BMPR-II) gene have been identified in patients with primary pulmonary hypertension. The mechanisms by which these mutations contribute to the pathogenesis of primary pulmonary hypertension are not fully elucidated. To assess the impact of a heterozygous mutation of the BMPR-II gene on the pulmonary vasculature, we studied mice carrying a mutant BMPR-II allele lacking exons 4 and 5 ( BMPR-II+/− mice). BMPR-II+/− mice had increased mean pulmonary arterial pressure and pulmonary vascular resistance compared with their wild-type littermates. Histological analyses revealed that the wall thickness of muscularized pulmonary arteries (<100 μm in diameter) and the number of alveolar-capillary units were greater in BMPR-II+/− than in wild-type mice. Breathing 11% oxygen for 3 wk increased mean pulmonary arterial pressure, pulmonary vascular resistance, and hemoglobin concentration to similar levels in BMPR-II+/− and wild-type mice, but the degree of muscularization of small pulmonary arteries and formation of alveolar-capillary units were reduced in BMPR-II+/− mice. Our results suggest that, in mice, mutation of one copy of the BMPR-II gene causes pulmonary hypertension but impairs the ability of the pulmonary vasculature to remodel in response to prolonged hypoxic breathing.

Serotonin transporter is not required for the development of severe pulmonary hypertension in the Sugen hypoxia rat model

2015 ◽  
Vol 309 (10) ◽  
pp. L1164-L1173 ◽  
Author(s):  
Michiel Alexander de Raaf ◽  
Yvet Kroeze ◽  
Anthonieke Middelman ◽  
Frances S. de Man ◽  
Helma de Jong ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Serotonin Transporter ◽  
Rat Model ◽  
Systolic Pressure ◽  
Serum Levels ◽  
Normal Function ◽  
Ventricular Systolic Pressure ◽  
Serotonin System ◽  
Pulmonary Arterial

Increased serotonin serum levels have been proposed to play a key role in pulmonary arterial hypertension (PAH) by regulating vessel tone and vascular smooth muscle cell proliferation. An intact serotonin system, which critically depends on a normal function of the serotonin transporter (SERT), is required for the development of experimental pulmonary hypertension in rodents exposed to hypoxia or monocrotaline. While these animal models resemble human PAH only with respect to vascular media remodeling, we hypothesized that SERT is likewise required for the presence of lumen-obliterating intima remodeling, a hallmark of human PAH reproduced in the Sugen hypoxia (SuHx) rat model of severe angioproliferative pulmonary hypertension. Therefore, SERT wild-type (WT) and knockout (KO) rats were exposed to the SuHx protocol. SERT KO rats, while completely lacking SERT, were hemodynamically indistinguishable from WT rats. After exposure to SuHx, similar degrees of severe angioproliferative pulmonary hypertension and right ventricular hypertrophy developed in WT and KO rats (right ventricular systolic pressure 60 vs. 55 mmHg, intima thickness 38 vs. 30%, respectively). In conclusion, despite its implicated importance in PAH, SERT does not play an essential role in the pathogenesis of severe angioobliterative pulmonary hypertension in rats exposed to SuHx.

Safflower injection inhibits pulmonary arterial remodeling in a monocrotaline-induced pulmonary arterial hypertension rat model

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Aifeng Chen ◽  
Shibiao Ding ◽  
Liangliang Kong ◽  
Jianpu Xu ◽  
Fei He ◽  
...  
Keyword(s):  
Growth Factor ◽  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Cardiac Muscle ◽  
Rat Model ◽  
Dependent Manner ◽  
Arterial Remodeling ◽  
Pulmonary Arterial ◽  
Dose Dependent

AbstractPulmonary arterial hypertension (PAH) is a group of diseases with an increase of pulmonary artery pressure (PAP) and pulmonary vascular resistance. Here, the effects of safflower injection, a preparation of Chinese herbs, was investigated in a monocrotaline (MCT)-induced PAH rat model. PAP, carotid artery pressure (CAP), and the right ventricular hypertrophy index (RVHI) increased in the PAH group, while safflower injection was able to inhibit this increase to similar levels as observed in the normal group. The arteriole wall of the lungs and cardiac muscle were thickened and edema was observed in the PAH group, while these pathologies were improved in the herb-treated group in a dose-dependent manner. MCT treatment induced proliferation of pulmonary artery smooth muscle cells (PASMCs), which was inhibited by safflower injection in a dose-dependent manner. Our experimental results demonstrated that safflower injection can regulate pulmonary arterial remodeling through affecting the expression of connective tissue growth factor, transforming growth factor-β, integrin, collagen or fibronectin, which subsequently affected the thicknesses of the arteriole walls of the lungs and cardiac muscle, and thereby benefits the control of PAH. This means safflower injection improved the abnormalities in PAP, CAP and RVHI, and pulmonary arterial remodeling through regulation of remodeling factors.

scholarly journals Risk stratification in PAH

2020 ◽  
Vol 2020 (1) ◽  
Author(s):  
Paul A Corris
Keyword(s):  
Heart Failure ◽  
Pulmonary Arteries ◽  
Right Heart Failure ◽  
Response To Therapy ◽  
Pulmonary Vasculature ◽  
Short Term ◽  
Right Heart ◽  
Term Survival ◽  
Pulmonary Arterial ◽  
Short Term Survival

[No abstract. Showing first paragraph of article]Pulmonary arterial hypertension (PAH) is a chronic disease of the pulmonary vasculature characterized by progressive narrowing of the pulmonary arteries leading to increased pulmonary vascular resistance, right heart failure, and ultimately premature death.There has been a significant improvement in the available medical therapeutic options in this field that have impacted the short-term survival and morbidity in these patients. However, the median survival post-diagnosis remains unacceptable at 7 years.Physicians’ ability to predict PAH disease progression and risk allows them to determine the patient’s prognosis, make informed adjustments to therapy, and monitor his or her response to therapy . If widely adopted, risk prediction can enhance the consistency of treatment approaches and improve the timeliness of referral for lung transplantation. This approach should lead optimal, directed care that ultimately reduces morbidity and improves mortality in patients with PAH.

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