04 February 2019 by Jeffrey Fineman

Pulmonary vascular disease associated with congenital heart disease: comparison of ovine models to translate natural history into pathobiology


The natural history of pulmonary vascular disease (PVD) associated with congenital heart disease (CHD) depends upon associated hemodynamics. Patients exposed to increased pulmonary blood flow (PBF) and pulmonary arterial pressure (PAP) develop PVD more commonly than patients exposed to increased PBF alone. The different hemodynamic forces associated with different CHD lesions are presumed to account for observed differences in the natural history of PVD; however, the underlying pathobiological mechanisms are unknown.


To investigate the effects of differing mechanical forces on physiologic and molecular responses.


We developed two models of CHD utilizing fetal surgical techniques: 1) left pulmonary artery (LPA) ligation 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 to controls. RNA Sequencing revealed excellent separation between groups via both principal components analysis and unsupervised hierarchical clustering. 609 transcripts were up-regulated in shunt PAECs relative to control cells and 947 transcripts were down-regulated. There were fewer differentially expressed transcripts observed in the comparison of LPA and control PAECs in which 47 transcripts were found to be up-regulated and 147 were found to be down-regulated. In PAECs from shunt but not LPA or control lambs, Gene Ontology analysis demonstrated enrichment for biologic processes such as angiogenesis and vascular development and the negative regulation of apoptosis. Consistent with this analysis, we found hyperproliferation, 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 PH associated with CHD

Key Contributors

Jeffrey R. Fineman 1,2, Rebecca Johnson Kameny 1, Jason B. Boehme 1, Catherine Morris 1, Terry Zhu 1, Eric G. Johnson 3, Csaba Galambos 4, Gary W. Raff 5, Samuel R. Chiacchia 1, Qing Lu 6, Stephen M. Black 6, Emin Maltepe 1, and Sanjeev A. Datar 1 : 1 Department of Pediatrics, University of California, San Francisco, San Francisco, CA. 2 Cardiovascular Research Institute, University of California, San Francisco. 3 Department of Veterinary Surgical and Radiological Sciences, School of Veterinary Medicine, University of California-Davis, Davis, CA. 4 Departments of Pathology and Laboratory Medicine, University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora, Colorado. 5 Department of Surgery, University of California, Davis, Davis, CA. 6 Department of Medicine, University of Arizona, Tucson, AZ.

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