Pulmonary Artery Endothelial Cell Phenotype Switch Impairs Angiogenesis in the Lungs in Persistent Pulmonary Hypertension of the Newborn

Abstract Background: Pulmonary artery endothelial cell (PAEC) inflammation is a critical event in the development of pulmonary arterial hypertension (PAH). However, the pathogenesis of PAEC inflammation remains unclear. Methods: Purified recombinant human inhibitor of κB kinase subunit β (IKKβ) protein, human PAECs and monocrotaline-induced pulmonary hypertensive rats were employed in the study. Site-directed mutagenesis, gene knockdown or overexpression were conducted to manipulate the expression or activity of a target protein. Results: We showed that hydrogen sulfide (H2S) inhibited IKKβ activation in the cell model of human PAEC inflammation induced by monocrotaline pyrrole-stimulation or knockdown of cystathionine γ-lyase (CSE), an H2S generating enzyme. Mechanistically, H2S was proved to inhibit IKKβ activity directly via sulfhydrating IKKβ at cysteinyl residue 179 (C179) in purified recombinant IKKβ protein in vitro, whereas thiol reductant dithiothreitol (DTT) reversed H2S-induced IKKβ inactivation. Furthermore, to demonstrate the significance of IKKβ sulfhydration by H2S in the development of PAEC inflammation, we mutated C179 to serine (C179S) in IKKβ. In purified IKKβ protein, C179S mutation of IKKβ abolished H2S-induced IKKβ sulfhydration and the subsequent IKKβ inactivation. In human PAECs, C179S mutation of IKKβ blocked H2S-inhibited IKKβ activation and PAEC inflammatory response. In pulmonary hypertensive rats, C179S mutation of IKKβ abolished the inhibitory effect of H2S on IKKβ activation and pulmonary vascular inflammation and remodeling. Conclusion: Collectively, our in vivo and in vitro findings demonstrated, for the first time, that endogenous H2S directly inactivated IKKβ via sulfhydrating IKKβ at Cys179 to inhibit nuclear factor-κB (NF-κB) pathway activation and thereby control PAEC inflammation in PAH.

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Retraction notice to ICAM-1 PROMOTES THE ABNORMAL ENDOTHELIAL CELL PHENOTYPE IN CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION

The Journal of Heart and Lung Transplantation ◽

10.1016/j.healun.2021.01.1563 ◽

2021 ◽

Vol 40 (4) ◽

pp. 318

Author(s):

Jennifer Arthur Ataam ◽

Olaf Mercier ◽

Lilia Lamrani ◽

Myriam Amsallem ◽

Joanna Arthur Ataam ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Endothelial Cell ◽

Chronic Thromboembolic Pulmonary Hypertension ◽

Cell Phenotype ◽

Thromboembolic Pulmonary Hypertension ◽

Retraction Notice

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

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00043.2013 ◽

2013 ◽

Vol 304 (12) ◽

pp. L894-L901 ◽

Cited By ~ 25

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.

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An unusual cause of refractory persistent pulmonary hypertension of the newborn: anomalous origin of one pulmonary artery

Cardiology in the Young ◽

10.1017/s1047951113000826 ◽

2013 ◽

Vol 24 (3) ◽

pp. 543-545

Author(s):

Nilufer Guzoglu ◽

Fatma Nur Sari ◽

Nahide Altug

Keyword(s):

Pulmonary Hypertension ◽

Pulmonary Artery ◽

Innominate Artery ◽

Persistent Pulmonary Hypertension ◽

Anomalous Origin ◽

Cardiac Malformation ◽

Mortality And Morbidity ◽

Congenital Cardiac Malformation

AbstractPersistent pulmonary hypertension of the newborn is a source of considerable mortality and morbidity. Anomalous origin of one pulmonary artery, an uncommon congenital cardiac malformation, is a rare cause of persistent pulmonary hypertension. Here, we report the case of a patient with an anomalous origin of one pulmonary artery from the innominate artery who presented with persistent pulmonary hypertension refractory to treatment.

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Intrauterine growth restriction decreases pulmonary alveolar and vessel growth and causes pulmonary artery endothelial cell dysfunction in vitro in fetal sheep

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00197.2011 ◽

2011 ◽

Vol 301 (6) ◽

pp. L860-L871 ◽

Cited By ~ 120

Author(s):

Paul J. Rozance ◽

Gregory J. Seedorf ◽

Alicia Brown ◽

Gates Roe ◽

Meghan C. O'Meara ◽

...

Keyword(s):

Endothelial Cell ◽

Cell Growth ◽

Pulmonary Artery ◽

Intrauterine Growth Restriction ◽

Tube Formation ◽

No Production ◽

Vascular Growth ◽

Intrauterine Growth ◽

Pulmonary Artery Endothelial Cell

Intrauterine growth restriction (IUGR) increases the risk for bronchopulmonary dysplasia (BPD). Abnormal lung structure has been noted in animal models of IUGR, but whether IUGR adversely impacts fetal pulmonary vascular development and pulmonary artery endothelial cell (PAEC) function is unknown. We hypothesized that IUGR would decrease fetal pulmonary alveolarization, vascular growth, and in vitro PAEC function. Studies were performed in an established model of severe placental insufficiency and IUGR induced by exposing pregnant sheep to elevated temperatures. Alveolarization, quantified by radial alveolar counts, was decreased 20% ( P < 0.005) in IUGR fetuses. Pulmonary vessel density was decreased 44% ( P < 0.01) in IUGR fetuses. In vitro, insulin increased control PAEC migration, tube formation, and nitric oxide (NO) production. This response was absent in IUGR PAECs. VEGFA stimulated tube formation, and NO production also was absent. In control PAECs, insulin increased cell growth by 68% ( P < 0.0001). Cell growth was reduced in IUGR PAECs by 29% at baseline ( P < 0.01), and the response to insulin was attenuated ( P < 0.005). Despite increased basal and insulin-stimulated Akt phosphorylation in IUGR PAECs, endothelial NO synthase (eNOS) protein expression as well as basal and insulin-stimulated eNOS phosphorylation were decreased in IUGR PAECs. Both VEGFA and VEGFR2 also were decreased in IUGR PAECs. We conclude that fetuses with IUGR are characterized by decreased alveolar and vascular growth and PAEC dysfunction in vitro. This may contribute to the increased risk for adverse respiratory outcomes and BPD in infants with IUGR.

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Management of Persistent Pulmonary Hypertension After Correction of Congenital Heart Defect with Autologous Marrow-Derived Mononuclear Stem Cell Injection into the Pulmonary Artery: A Pilot Study

Pediatric Cardiology ◽

10.1007/s00246-019-02273-2 ◽

2020 ◽

Vol 41 (2) ◽

pp. 398-406

Author(s):

Hamid Amoozgar ◽

Pegah Banafi ◽

Hamid Mohammadi ◽

Mohammad Reza Edraki ◽

Nima Mehdizadegan ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Stem Cell ◽

Pilot Study ◽

Pulmonary Artery ◽

Congenital Heart Defect ◽

Congenital Heart ◽

Persistent Pulmonary Hypertension ◽

Cell Injection ◽

Heart Defect ◽

Stem Cell Injection

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Dirofilaria immitis: heartworm infection alters pulmonary artery endothelial cell behavior

Journal of Applied Physiology ◽

10.1152/jappl.1997.82.2.389 ◽

1997 ◽

Vol 82 (2) ◽

pp. 389-398 ◽

Cited By ~ 18

Author(s):

Maria Mupanomunda ◽

Jeffrey F. Williams ◽

Charles D. Mackenzie ◽

Lana Kaiser

Keyword(s):

Nitric Oxide ◽

Smooth Muscle ◽

Endothelial Cell ◽

Pulmonary Artery ◽

Dirofilaria Immitis ◽

Cell Behavior ◽

A 23187 ◽

Heartworm Infection ◽

Endothelium Dependent Relaxation ◽

Pulmonary Artery Endothelial Cell

Mupanomunda, Maria, Jeffrey F. Williams, Charles D. Mackenzie, and Lana Kaiser. Dirofilaria immitis:heartworm infection alters pulmonary artery endothelial cell behavior. J. Appl. Physiol. 82(2): 389–398, 1997.—The pathogenesis of filariasis has generally been attributed to either physical presence of the adult parasites or the host’s immune response to the parasites. However, the spectrum of filariasis cannot be entirely explained by these causes, and other mechanisms must be operative. It is now evident that factors released by filarial parasites likely contribute to the pathogenesis of filarial diseases. Adult heartworms ( Dirofilaria immitis) reside in the right heart and pulmonary artery, so the pulmonary artery should be exposed to the highest concentration of filarial factors. We tested the hypothesis that endothelium-dependent relaxation is altered in the in vitro pulmonary artery from heartworm-infected dogs. Relaxation responses to endothelium-dependent vasodilators (methacholine, bradykinin, substance P, and A-23187) and the non-endothelium-dependent vasodilator nitroglycerin and contractile responses were measured in rings of pulmonary artery from control and heartworm-infected dogs. Endothelium-dependent relaxation was assessed in the presence and absence of inhibitors of nitric oxide synthase, cyclooxygenase, and guanylate cyclase. Responses to methacholine, substance P, and A-23187, but not to bradykinin, nitroglycerin, norepinephrine, or KCl, were depressed in pulmonary artery from heartworm-infected dogs when compared with control, suggesting that changes in endothelial cell and not vascular smooth muscle behavior are involved in altered relaxation. The mechanism of endothelium-dependent relaxation in control pulmonary artery appears to involve nitric oxide in the case of methacholine and both nitric oxide and a cyclooxygenase product in the case of bradykinin and A-23187. The mechanism of endothelium-dependent relaxation in pulmonary artery from heartworm-infected dogs was not clearly elucidated. These data provide no evidence that heartworm infection globally influences either endothelial cell receptor function or the vascular smooth muscle guanylate cyclase guanosine 3′,5′-cyclic monophosphate system, making it likely that changes in intracellular signaling are primarily responsible for the observed alteration of endothelium-mediated relaxation. Alteration of endothelial cell function by filarial parasites may be an important component in the pathology associated with filariasis.

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