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Pulmonary Arterial Hypertension and Endothelial Dysfunction Is Linked to NADPH Oxidase-Derived Superoxide Formation in Venous Thrombosis and Pulmonary Embolism in Mice.

ABSTRACT: Pulmonary embolism (PE) results from deep vein thrombosis (DVT) and can lead to chronic thromboembolic pulmonary hypertension (CTEPH) involving vascular dysfunction. Mechanisms are incompletely understood, in part due to lack of mouse models. We induced PE in C57BL/6 mice by intravenous injection of thrombin (166?U/kg BW), confirmed by a sudden bradycardia, bradypnea, and an increase in pulmonary artery (PA) pressure observed by high-frequency ultrasound. While symptoms resolved rapidly after single thrombin application, repeated PEs resulted in sustained PA-pressure increase, increased PA superoxide formation assessed by oxidative fluorescent microtopography, increased PA gp91^phox expression, and endothelial dysfunction assessed by isometric tension studies of isolated PA segments after 24 hours. DVT was modeled in C57BL/6 mice by ligation of the inferior vena cava (IVC). Importantly, small pulmonary emboli could be detected along with a mild phenotype of PA endothelial dysfunction and oxidative stress in the absence of PA-pressure elevation. mRNA expression of plasminogen activator inhibitor-1 was increased in PAs of mice with recurrent PE after repetitive thrombin injections and to a lesser extent in DVT mice. In summary, our data suggest that PA endothelial dysfunction, induced by gp91^phox-derived ROS, is an early event upon repetitive PE. This phenomenon might help to elucidate the mechanisms of PA dysfunction in the pathogenesis of CTEPH.

SUBMITTER: Brandt M

PROVIDER: S-EPMC6015670 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Pulmonary Arterial Hypertension and Endothelial Dysfunction Is Linked to NADPH Oxidase-Derived Superoxide Formation in Venous Thrombosis and Pulmonary Embolism in Mice.

Brandt Moritz M Giokoglu Eleni E Garlapati Venkata V Bochenek Madgalena L ML Molitor Michael M Hobohm Lukas L Schönfelder Tanja T Münzel Thomas T Kossmann Sabine S Karbach Susanne H SH Schäfer Katrin K Wenzel Philip P

Oxidative medicine and cellular longevity 20180610

Pulmonary embolism (PE) results from deep vein thrombosis (DVT) and can lead to chronic thromboembolic pulmonary hypertension (CTEPH) involving vascular dysfunction. Mechanisms are incompletely understood, in part due to lack of mouse models. We induced PE in C57BL/6 mice by intravenous injection of thrombin (166 U/kg BW), confirmed by a sudden bradycardia, bradypnea, and an increase in pulmonary artery (PA) pressure observed by high-frequency ultrasound. While symptoms resolved rapidly after si ...[more]

PMID: 29983855

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Project description:Pulmonary vascular arterial remodeling is an integral and well-understood component of pulmonary hypertension (PH). In contrast, morphological alterations of pulmonary veins in PH are scarcely described. Explanted lungs (n = 101) from transplant recipients with advanced chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary arterial hypertension (IPAH) were analyzed for venous vascular involvement according to a pre-specified, semi-quantitative grading scheme, which categorizes the intensity of venous remodeling in three groups of incremental severity: venous hypertensive (VH) grade 0 = characterized by an absence of venous vascular remodeling; VH grade 1 = defined by a dominance of either arterialization or intimal fibrosis; and VH grade 2 = a substantial composite of arterialization and intimal fibrosis. Patients were grouped according to clinical and hemodynamic characteristics in three groups: COPD non-PH, COPD-PH, and IPAH, respectively. Histological specimens were examined by a cardiovascular pathologist blinded to clinical and hemodynamic data. Pathological alterations of pulmonary veins were present in all hemodynamic groups, with the following incidences of VH grade 0/1/2: 34/66/0% in COPD non-PH; 19/71/10% in COPD-PH; and 11/61/28% in IPAH. In COPD, explorative correlation analysis of venous remodeling suggested a modest positive correlation with systolic and mean pulmonary artery pressure ( P = 0.032, respectively) and an inverse modest correlation with diffusion capacity for carbon monoxide ( P = 0.027). In addition, venous remodeling correlated positively with the degree of arterial remodeling ( P = 0.014). In COPD-PH and IPAH, advanced forms of pulmonary venous remodeling are present, emphasizing that the disease is not exclusively restricted to arterial lesions. In addition, venous remodeling may be related to the hemodynamic severity, but more rigorous analysis is required to clearly define potential relationships.

Project description:BackgroundPulmonary hypertension is a heterogeneous disease, and a significant portion of patients at risk for it have CT imaging available. Advanced automated processing techniques could be leveraged for early detection, screening, and development of quantitative phenotypes. Pruning and vascular tortuosity have been previously described in pulmonary arterial hypertension (PAH), but the extent of these phenomena in arterial vs venous pulmonary vasculature and in exercise pulmonary hypertension (ePH) have not been described.Research questionWhat are the arterial and venous manifestations of pruning and vascular tortuosity using CT imaging in PAH, and do they also occur in ePH?Study design and methodsA cohort of patients with PAH and ePH and control subjects with available CT angiograms were retrospectively identified to examine the differential arterial and venous presence of pruning and tortuosity in patients with precapillary pulmonary hypertension not confounded by lung or thromboembolic disease. The pulmonary vasculature was reconstructed, and an artificial intelligence method was used to separate arteries and veins and to compute arterial and venous vascular volumes and tortuosity.ResultsA total of 42 patients with PAH, 12 patients with ePH, and 37 control subjects were identified. There was relatively lower (median [interquartile range]) arterial small vessel volume in subjects with PAH (PAH 14.7 [11.7-16.5; P < .0001]) vs control subjects (16.9 [15.6-19.2]) and venous small vessel volume in subjects with PAH and ePH (PAH 8.0 [6.5-9.6; P < .0001]; ePH, 7.8 [7.5-11.4; P = .004]) vs control subjects (11.5 [10.6-12.2]). Higher large arterial volume, however, was only observed in the pulmonary arteries (PAH 17.1 [13.6-23.4; P < .0001] vs control subjects 11.4 [8.1-15.4]). Similarly, tortuosity was higher in the pulmonary arteries in the PAH group (PAH 3.5 [3.3-3.6; P = .0002] vs control 3.2 [3.2-3.3]).InterpretationLower small distal pulmonary vascular volume, higher proximal arterial volume, and higher arterial tortuosity were observed in PAH. These can be quantified by using automated techniques from clinically acquired CT scans of patients with ePH and resting PAH.

Dataset Information

Pulmonary Arterial Hypertension and Endothelial Dysfunction Is Linked to NADPH Oxidase-Derived Superoxide Formation in Venous Thrombosis and Pulmonary Embolism in Mice.

Publications

Pulmonary Arterial Hypertension and Endothelial Dysfunction Is Linked to NADPH Oxidase-Derived Superoxide Formation in Venous Thrombosis and Pulmonary Embolism in Mice.

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