Ovine Models of Congenital Heart Disease and the Consequences of Hemodynamic Alterations for Pulmonary Artery Remodeling
Autor: | Stephen M. Black, Sanjeev A. Datar, Eric G. Johnson, Gary W. Raff, Terry Zhu, Ting Wang, Csaba Galambos, Qing Lu, Brian D. Goudy, Catherine Morris, Jeffrey R. Fineman, Xutong Sun, Jason B. Boehme, Rebecca J Kameny, Emin Maltepe, Samuel R. Chiacchia |
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Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Pulmonary Circulation Heart disease Clinical Biochemistry Respiratory System Hemodynamics Cardiorespiratory Medicine and Haematology Cardiovascular endothelial dysfunction 0302 clinical medicine Pregnancy mechanical forces pulmonary hypertension 2.1 Biological and endogenous factors Endothelial dysfunction Aetiology Lung Aorta Pediatric Pulmonary Arterial Hypertension Left pulmonary artery congenital heart disease medicine.anatomical_structure Heart Disease Cardiology Female Pulmonary and Respiratory Medicine medicine.medical_specialty Heart Ventricles Primary Cell Culture Bioengineering Pulmonary Artery Vascular Remodeling Nitric Oxide 03 medical and health sciences Fetus Afterload Pulmonary Heart Disease medicine.artery Internal medicine medicine Animals Humans Arterial Pressure Molecular Biology Cell Proliferation Sheep business.industry Animal Endothelial Cells Cell Biology medicine.disease Pulmonary hypertension Disease Models Animal Major Technical Advances 030104 developmental biology Good Health and Well Being 030228 respiratory system Coronary Occlusion Ventricle Pulmonary artery Disease Models pulmonary vascular disease Congenital Structural Anomalies business |
Zdroj: | Am J Respir Cell Mol Biol American journal of respiratory cell and molecular biology, vol 60, iss 5 |
ISSN: | 1535-4989 |
Popis: | The natural history of pulmonary vascular disease associated with congenital heart disease (CHD) depends on associated hemodynamics. Patients exposed to increased pulmonary blood flow (PBF) and pulmonary arterial pressure (PAP) develop pulmonary vascular disease more commonly than patients exposed to increased PBF alone. To investigate the effects of these differing mechanical forces on physiologic and molecular responses, we developed two models of CHD using fetal surgical techniques: 1) left pulmonary artery (LPA) ligation primarily resulting in increased PBF and 2) aortopulmonary shunt placement resulting in increased PBF and PAP. Hemodynamic, histologic, and molecular studies were performed on control, LPA, and shunt lambs as well as pulmonary artery endothelial cells (PAECs) derived from each. Physiologically, LPA, and to a greater extent shunt, lambs demonstrated an exaggerated increase in PAP in response to vasoconstricting stimuli compared with controls. These physiologic findings correlated with a pathologic increase in medial thickening in pulmonary arteries in shunt lambs but not in control or LPA lambs. Furthermore, in the setting of acutely increased afterload, the right ventricle of control and LPA but not shunt lambs demonstrates ventricular-vascular uncoupling and adverse ventricular-ventricular interactions. RNA sequencing revealed excellent separation between groups via both principal components analysis and unsupervised hierarchical clustering. In addition, we found hyperproliferation of PAECs from LPA lambs, and to a greater extent shunt lambs, with associated increased angiogenesis and decreased apoptosis in PAECs derived from shunt lambs. A further understanding of mechanical force-specific drivers of pulmonary artery pathology will enable development of precision therapeutics for pulmonary hypertension associated with CHD. |
Databáze: | OpenAIRE |
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