Ovine models of congenital heart disease and the consequences of hemodynamic alterations for pulmonary artery remodeling

Rebecca Johnson Kameny, Sanjeev A. Datar, Jason B. Boehme, Catherine Morris, Terry Zhu, Brian D. Goudy, Eric G. Johnson, Csaba Galambos, Gary W. Raff, Xutong Sun, Ting Wang, Samuel R. Chiacchia, Qing Lu, Stephen M. Black, Emin Maltepe, Jeffrey R. Fineman

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)503-514
Number of pages12
JournalAmerican journal of respiratory cell and molecular biology
Volume60
Issue number5
DOIs
Publication statusPublished - May 1 2019

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Keywords

  • Congenital heart disease
  • Endothelial dysfunction
  • Mechanical forces
  • Pulmonary hypertension
  • Pulmonary vascular disease

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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