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1. Mechanical forces alter endothelin-1 signaling: comparative ovine models of congenital heart disease

Author

Terry Zhu, Samuel Chiacchia, Rebecca J. Kameny, Antoni Garcia De Herreros, Wenhui Gong, Gary W. Raff, Jason B. Boehme, Emin Maltepe, Juan C. Lasheras, Stephen M. Black, Sanjeev A. Datar, and Jeffrey R. Fineman

Subjects
Diseases of the circulatory (Cardiovascular) system, RC666-701, Diseases of the respiratory system, RC705-779
Abstract

The risk and progression of pulmonary vascular disease in patients with congenital heart disease is dependent on the hemodynamics associated with different lesions. However, the underlying mechanisms are not understood. Endothelin-1 is a potent vasoconstrictor that plays a key role in the pathology of pulmonary vascular disease. We utilized two ovine models of congenital heart disease: (1) fetal aortopulmonary graft placement (shunt), resulting in increased flow and pressure; and (2) fetal ligation of the left pulmonary artery resulting in increased flow and normal pressure to the right lung, to investigate the hypothesis that high pressure and flow, but not flow alone, upregulates endothelin-1 signaling. Lung tissue and pulmonary arterial endothelial cells were harvested from control, shunt, and the right lung of left pulmonary artery lambs at 3–7 weeks of age. We found that lung preproendothelin-1 mRNA and protein expression were increased in shunt lambs compared to controls. Preproendothelin-1 mRNA expression was modestly increased, and protein was unchanged in left pulmonary artery lambs. These changes resulted in increased lung endothelin-1 levels in shunt lambs, while left pulmonary artery levels were similar to controls. Pulmonary arterial endothelial cells exposed to increased shear stress decreased endothelin-1 levels by five-fold, while cyclic stretch increased levels by 1.5-fold. These data suggest that pressure or an additive effect of pressure and flow, rather than increased flow alone, is the principal driver of increased endothelin signaling in congenital heart disease. Defining the molecular drivers of the pathobiology of pulmonary vascular disease due to differing mechanical forces will allow for a more targeted therapeutic approach.

Published
2020
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2. Ovine Models of Congenital Heart Disease and the Consequences of Hemodynamic Alterations for Pulmonary Artery Remodeling

Author

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, and Samuel R. Chiacchia

Subjects
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
Abstract

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.

Published
2019

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