scholarly journals Gestational long-term hypoxia induces metabolomic reprogramming and phenotypic transformations in fetal sheep pulmonary arteries

2021 ◽  
Author(s):  
Eric Leslie ◽  
Vanessa Lopez ◽  
Nana A.O. Anti ◽  
Rafael Alvarez ◽  
Isaac Kafeero ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arteries ◽  
Metabolic Reprogramming ◽  
Persistent Pulmonary Hypertension ◽  
Wall Thickening ◽  
Omega 3 ◽  
Alpha Linolenic Acid ◽  
Fetal Sheep ◽  
Functional Changes

Gestational long-term hypoxia increases the risk of myriad diseases in infants including persistent pulmonary hypertension. Similar to humans, fetal lamb lung development is susceptible to long-term intrauterine hypoxia, with structural and functional changes associated with the development of pulmonary hypertension including pulmonary arterial medial wall thickening and dysregulation of arterial reactivity, which culminates in decreased right ventricular output. To further explore the mechanisms associated with hypoxia-induced aberrations in the fetal sheep lung, we examined the premise that metabolomic changes and functional phenotypic transformations occur due to intrauterine, long-term hypoxia. To address this, we performed electron microscopy, Western immunoblotting, calcium imaging, and metabolomic analyses on pulmonary arteries isolated from near-term fetal lambs that had been exposed to low- or high-altitude (3801 m) hypoxia for the latter 110+ days of gestation. Our results demonstrate that the sarcoplasmic reticulum was swollen with high luminal width and distances to the plasma membrane in the hypoxic group. Hypoxic animals presented with higher endoplasmic reticulum stress and suppressed calcium storage. Metabolically, hypoxia was associated with lower levels of multiple omega-3 polyunsaturated fatty acids and derived lipid mediators (e.g. eicosapentanoic acid, docosahexaenoic acid, alpha-linolenic acid, 5-hydroxyeicosapentaenoic acid (5-HEPE), 12-HEPE, 15-HEPE, prostaglandin E3, and 19(20)-epoxydocosapentaenoic acid), and higher levels of some omega-6 metabolites (p<0.02) including 15-Keto prostaglandin E2 and linoleoylglycerol. Collectively, the results reveal broad evidence for long-term hypoxia-induced metabolic reprogramming and phenotypic transformations in the pulmonary arteries of fetal sheep, conditions that likely contribute to the development of persistent pulmonary hypertension.

Persistent Pulmonary Hypertension of the Newborn: Role of Nitric Oxide

1995 ◽  
Vol 10 (6) ◽  
pp. 270-282
Author(s):  
Stella Kourembanas
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Structural Changes ◽  
Critical Role ◽  
Persistent Pulmonary Hypertension ◽  
Cell Contractility ◽  
Vasoactive Mediators ◽  
Nitric Oxide Therapy

Persistent pulmonary hypertension of the newborn (PPHN) is a common cause of respiratory failure in the full-term neonate. Molecular and cellular studies in vascular biology have revealed that endothelial-derived mediators play a critical role in the pathogenesis and treatment of PPHN. Endothelial-derived vasoconstrictors, like endothelin, may increase smooth muscle cell contractility and growth, leading to the physiologic and structural changes observed in the pulmonary arterioles of infants with this disease. On the other hand, decreased production of the endothelial-derived relaxing factor, nitric oxide, may exacerbate pulmonary vasoreactivity and lead to more severe pulmonary hypertension. Exogenous (inhaled) nitric oxide therapy reduces pulmonary vascular resistance and improves oxygenation. The safety and efficacy of this therapy in reducing the need for extracorporeal membrane oxygenation and decreasing long-term morbidity is being tested in several trials nationally and abroad. Understanding the basic mechanisms that regulate the gene expression and production of these vasoactive mediators will lead to improved preventive and therapeutic strategies for PPHN.

scholarly journals Serotonin contributes to high pulmonary vascular tone in a sheep model of persistent pulmonary hypertension of the newborn

2013 ◽  
Vol 304 (12) ◽  
pp. L894-L901 ◽  
Author(s):  
Cassidy Delaney ◽  
Jason Gien ◽  
Gates Roe ◽  
Nicole Isenberg ◽  
Jenai Kailey ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Tryptophan Hydroxylase ◽  
Late Gestation ◽  
Persistent Pulmonary Hypertension ◽  
Sheep Model ◽  
Pulmonary Hemodynamics ◽  
Fetal Sheep ◽  
Pulmonary Arterial

Although past studies demonstrate that altered serotonin (5-HT) signaling is present in adults with idiopathic pulmonary arterial hypertension, whether serotonin contributes to the pathogenesis of persistent pulmonary hypertension of the newborn (PPHN) is unknown. We hypothesized that 5-HT contributes to increased pulmonary vascular resistance (PVR) in a sheep model of PPHN and that selective 5-HT reuptake inhibitor (SSRI) treatment increases PVR in this model. We studied the hemodynamic effects of 5-HT, ketanserin (5-HT2A receptor antagonist), and sertraline, an SSRI, on pulmonary hemodynamics of the late gestation fetal sheep with PPHN caused by prolonged constriction of the ductus arteriosis. Brief intrapulmonary infusions of 5-HT increased PVR from 1.0 ± 0.07 (baseline) to 1.4 ± 0.22 mmHg/ml per minute of treatment ( P < 0.05). Ketanserin decreased PVR from 1.1 ± 0.15 (baseline) to 0.82 ± 0.09 mmHg/ml per minute of treatment ( P < 0.05). Sertraline increased PVR from 1.1 ± 0.17 (baseline) to 1.4 ± 0.17 mmHg/ml per minute of treatment ( P = 0.01). In addition, we studied 5-HT production and activity in vitro in experimental PPHN. Compared with controls, pulmonary artery endothelial cells from fetal sheep with PPHN exhibited increased expression of tryptophan hydroxylase 1 and 5-HT production by twofold and 56%, respectively. Compared with controls, 5-HT2A R expression was increased in lung homogenates and pulmonary artery smooth muscle cell lysates by 35% and 32%, respectively. We concluded that increased 5-HT contributes to high PVR in experimental PPHN through activation of the 5-HT2A receptor and that SSRI infusion further increases PVR in this model.

Disruption of cGMP production in pulmonary arteries isolated from fetal lambs with pulmonary hypertension

1995 ◽  
Vol 268 (4) ◽  
pp. H1483-H1489 ◽  
Author(s):  
R. H. Steinhorn ◽  
J. A. Russell ◽  
F. C. Morin
Keyword(s):  
Pulmonary Hypertension ◽  
Soluble Guanylate Cyclase ◽  
Ductus Arteriosus ◽  
Pulmonary Veins ◽  
Pulmonary Arteries ◽  
Fourth Generation ◽  
Response Curves ◽  
Fetal Sheep ◽  
A 23187 ◽  
Arteries And Veins

Ligation of the ductus arteriosus of the fetal sheep produces severe pulmonary hypertension at birth. Standard tissue bath techniques were used to study third- and fourth-generation pulmonary arteries and veins isolated from fetal sheep with pulmonary hypertension created by ligation of the ductus arteriosus 11–12 days before birth as well as from age-matched control sheep. Vessels pretreated with indomethacin and propranolol were submaximally preconstricted with norepinephrine before exposure to A-23187 (10(-8) to 3 x 10(-7) M), sodium nitroprusside (SNP; 10(-9) to 10(-5) M), and nitric oxide (NO) gas (1-973 ppm). Pulmonary veins in both control and ligated animals relaxed similarly and completely to A-23187, SNP, and NO. Control pulmonary arteries relaxed by 16 +/- 2% to A-23187 and relaxed completely to SNP and NO, with concentration-response curves shifted rightward of those observed in pulmonary veins. Pulmonary arteries from ligated animals did not relax at all to A-23187. SNP relaxations in ligated arteries were shifted rightward of control. Ligated arteries relaxed by only 11 +/- 5% to the highest dose of NO. However, control and ligated pulmonary arteries relaxed similarly to 8-bromoguanosine 3',5'-cyclic monophosphate (8-bromo-cGMP; 10(-5) to 10(-3) M) and atrial natriuretic peptide (10(-9) to 10(-7) M). These data are most simply explained by decreased arterial vascular smooth muscle sensitivity to NO at the level of soluble guanylate cyclase.

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 Chronic intrauterine pulmonary hypertension increases main pulmonary artery stiffness and adventitial remodeling in fetal sheep

2014 ◽  
Vol 307 (11) ◽  
pp. L822-L828 ◽  
Author(s):  
R. Blair Dodson ◽  
Matthew R. Morgan ◽  
Csaba Galambos ◽  
Kendall S. Hunter ◽  
Steven H. Abman
Keyword(s):  
Pulmonary Hypertension ◽  
Main Pulmonary Artery ◽  
Pulmonary Arteries ◽  
Clinical Syndrome ◽  
Late Gestation ◽  
Biaxial Testing ◽  
Mechanical Stiffness ◽  
Sheep Model ◽  
Fetal Sheep ◽  
Ecm Remodeling

Persistent pulmonary hypertension of the newborn (PPHN) is a clinical syndrome that is characterized by high pulmonary vascular resistance due to changes in lung vascular growth, structure, and tone. PPHN has been primarily considered as a disease of the small pulmonary arteries (PA), but proximal vascular stiffness has been shown to be an important predictor of morbidity and mortality in other diseases associated with pulmonary hypertension (PH). The objective of this study is to characterize main PA (MPA) stiffness in experimental PPHN and to determine the relationship of altered biomechanics of the MPA with changes in extracellular matrix (ECM) content and orientation of collagen and elastin fibers. MPAs were isolated from control and PPHN fetal sheep model and were tested by planar biaxial testing to measure stiffness in circumferential and axial vessel orientations. Test specimens were fixed for histological assessments of the vascular wall ECM constituents collagen and elastin. MPAs from PPHN sheep had increased mechanical stiffness ( P < 0.05) and altered ECM remodeling compared with control MPA. A constitutive mathematical model and histology demonstrated that PPHN vessels have a smaller contribution of elastin and a greater role for collagen fiber engagement compared with the control arteries. We conclude that exposure to chronic hemodynamic stress in late-gestation fetal sheep increases proximal PA stiffness and alters ECM remodeling. We speculate that proximal PA stiffness further contributes to increased right ventricular impedance in experimental PPHN, which contributes to abnormal transition of the pulmonary circulation at birth.

Oxidant stress from uncoupled nitric oxide synthase impairs vasodilation in fetal lambs with persistent pulmonary hypertension

2007 ◽  
Vol 292 (4) ◽  
pp. H1812-H1820 ◽  
Author(s):  
Girija G. Konduri ◽  
Ivane Bakhutashvili ◽  
Annie Eis ◽  
Kirkwood Pritchard
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Nitric Oxide Synthase ◽  
Pulmonary Artery ◽  
Ductus Arteriosus ◽  
Oxidant Stress ◽  
Pulmonary Arteries ◽  
Persistent Pulmonary Hypertension ◽  
Pulmonary Vasodilation ◽  
Oxide Synthase

Persistent pulmonary hypertension of newborn (PPHN) is associated with decreased NO release and impaired pulmonary vasodilation. We investigated the hypothesis that increased superoxide (O2•−) release by an uncoupled endothelial nitric oxide synthase (eNOS) contributes to impaired pulmonary vasodilation in PPHN. We investigated the response of isolated pulmonary arteries to the NOS agonist ATP and the NO donor S-nitroso- N-acetylpenicillamine (SNAP) in fetal lambs with PPHN induced by prenatal ligation of ductus arteriosus and in sham-ligated controls in the presence or absence of the NOS antagonist nitro-l-arginine methyl ester (l-NAME) or the O2•− scavenger 4,5-dihydroxy-1,3-benzenedisulfonate (Tiron). ATP caused dose-dependent relaxation of pulmonary artery rings in control lambs but induced constriction of the rings in PPHN lambs. l-NAME, the NO precursor l-arginine, and Tiron restored the relaxation response of pulmonary artery rings to ATP in PPHN. Relaxation to NO was attenuated in arteries from PPHN lambs, and the response was improved by l-NAME and by Tiron. We also investigated the alteration in heat shock protein (HSP)90-eNOS interactions and release of NO and O2•− in response to ATP in the pulmonary artery endothelial cells (PAEC) from these lambs. Cultured PAEC and endothelium of freshly isolated pulmonary arteries from PPHN lambs released O2•− in response to ATP, and this was attenuated by the NOS antagonist l-NAME and superoxide dismutase (SOD). ATP stimulated HSP90-eNOS interactions in PAEC from control but not PPHN lambs. HSP90 immunoprecipitated from PPHN pulmonary arteries had increased nitrotyrosine signal. Oxidant stress from uncoupled eNOS contributes to impaired pulmonary vasodilation in PPHN induced by ductal ligation in fetal lambs.

scholarly journals Chronic Thromboembolic Pulmonary Hypertension Medical Management

2021 ◽  
Vol 17 (2) ◽  
pp. e28-e32
Author(s):  
Ryan Logue ◽  
Zeenat Safdar
Keyword(s):  
Pulmonary Hypertension ◽  
Medical Management ◽  
Soluble Guanylate Cyclase ◽  
Pulmonary Arteries ◽  
Chronic Thromboembolic Pulmonary Hypertension ◽  
Standard Of Care ◽  
Pulmonary Angiography ◽  
Thromboembolic Pulmonary Hypertension ◽  
Soluble Guanylate Cyclase Stimulator

Chronic thromboembolic pulmonary hypertension (CTEPH) is a common long-term complication of pulmonary embolism characterized by thromboembolic obstruction of the pulmonary arteries, vascular arteriopathy, vascular remodeling, and ultimately pulmonary hypertension (PH). Although pulmonary endarterectomy (PEA) surgery is the standard of care, approximately 40% of patients in the international CTEPH registry were deemed inoperable. In addition to lifelong anticoagulation, the cornerstone of PH-specific medical management is riociguat, a soluble guanylate cyclase stimulator. Medical management should be started early in CTEPH patients and may be used as a bridge to PEA surgery or balloon pulmonary angiography. Medical management is indicated for inoperable CTEPH patients and patients who have recurrence of PH after PEA surgery.

scholarly journals Long-term outcomes after percutaneous transluminal pulmonary angioplasty for chronic thromboembolic pulmonary hypertension

2019 ◽  
Vol 16 (4) ◽  
pp. 27-32 ◽  
Author(s):  
Madina B Karabasheva ◽  
Nikolai M Danilov ◽  
Olesia V Sagaidak ◽  
Yurii G Matchin ◽  
Irina E Chazova
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arteries ◽  
Chronic Thromboembolic Pulmonary Hypertension ◽  
Treatment Method ◽  
Classical Type ◽  
Chronic Obstructive ◽  
Clinical Effects ◽  
Long Term Outcomes ◽  
Thromboembolic Pulmonary Hypertension

Introduction. Chronic thromboembolic pulmonary hypertension is a precapillary form of pulmonary hypertension that develops due to thrombotic mass obstruction of the pulmonary arteries. Balloon pulmonary angioplasty (BPA) is a new, alternative treatment method for inoperable chronic thromboembolic pulmonary hypertension (CTEPH), which demonstrated good hemodynamic and clinical effects. In this article we studied the long-term outcomes results after BPA. Material and methods. The study included 22 patients with inoperable CTEPH who were treated by BPA 6 (5; 8) interventions per patient. The results of the procedure were evaluated 2 months and 18 (12; 18) months after the last BPA. Results. A significant decrease in all important hemodynamic parameters was noted. There no difference between the date immediately after the operation and the long term period. However, the division of patients into groups with and without disease progression allow us to identify factors affecting the effectiveness of BPA (weight, the number of BPA procedures per patient, the total number of treated segmental arteries, the presence of coronary heart disease and chronic obstructive pulmonary disease, not the appointment of a concomitant pathogenetic pulmonary arterial hypertension (PAH) therapy. Conclusion. BPA is an effective method of treating patients with inoperable CTEPH, which demonstrates a good, sustainable long-term result. Patients with classical type 4 pulmonary hypertension receiving PAH-specific therapy are best responders to BPA.

Structure Function Correlates in the Pulmonary Vasculature during Acute Lung Injury and Chronic Pulmonary Hypertension

1991 ◽  
Vol 19 (4_part_1) ◽  
pp. 447-457 ◽  
Author(s):  
Barbara Meyrick
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Edema ◽  
Structural Changes ◽  
Pulmonary Arteries ◽  
Pulmonary Vasculature ◽  
Capillary Endothelium ◽  
Functional Changes ◽  
Structural Types ◽  
Chronic Pulmonary Hypertension ◽  
Hemodynamic Measurements

Arteries, veins, and capillaries comprise the pulmonary vasculature. Three structural types of artery and vein are identified, the most muscular vessels being the largest. For example, arteries that accompany the preacinar arteries are muscular in structure while those within the acinus may be either, muscular, partially muscular or non-muscular. These small intraacinar arteries contribute much to the hemodynamic behavior of the lung. Pulmonary edema results from damage to the capillary endothelium while chronic pulmonary hypertension is characterized by structural alterations in the pulmonary arteries. Correlation of the structural and functional changes of chronic pulmonary hypertension suggest that the increases in medial and adventitial thickness of the muscular preacinar arteries are secondary to the onset of this disease, while the changes in the peripheral arteries—appearance of muscle in smaller intraacinar arteries than normal and reduction in arterial volume—contribute to the rise in pulmonary artery pressure and pulmonary vascular resistance. Such correlations of structure and hemodynamic measurements demand that the lung be fixed in a simple and standardized manner. Available methodology to evaluate the structural changes that occur during the development of pulmonary edema and chronic pulmonary hypertension are described.

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