Pulmonary artery endothelial cell phenotypic alterations in a large animal model of pulmonary arteriovenous malformations after the Glenn shunt

Minoo N. Kavarana, Rupak Mukherjee, Shaina R. Eckhouse, William F. Rawls, Christina Logdon, Robert E. Stroud, Risha K. Patel, Elizabeth K. Nadeau, Francis G. Spinale, Eric M. Graham, Geoffrey A. Forbus, Scott M. Bradley, John S. Ikonomidis, Jeffrey A. Jones

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Background Longevity of the superior cavopulmonary connection (SCPC) is limited by the development of pulmonary arteriovenous malformations (PAVM). The goal of this study was to determine whether phenotypic changes in pulmonary artery endothelial cells (PAEC) that favor angiogenesis occur with PAVM formation. Methods A superior vena cava to right pulmonary artery connection was constructed in 5 pigs. Pulmonary arteries were harvested at 6 to 8 weeks after surgery to establish cultures of PAEC and smooth muscle cells, to determine cell proliferation, gene expression, and tubule formation. Abundance of proteins related to angiogenesis was measured in lung tissue. Results Contrast echocardiography revealed right-to-left shunting, consistent with PAVM formation. While the proliferation of smooth muscle cells from the right pulmonary artery (shunted side) and left pulmonary artery (nonshunted side) were similar, right PAEC proliferation was significantly higher. Expression profiles of genes encoding cellular signaling proteins were higher in PAECs from the right pulmonary artery versus left pulmonary artery. Protein abundance of angiopoietin-1, and Tie-2 (angiopoietin receptor) were increased in the right lung (both p < 0.05). Tubule formation was increased in endothelial cells from the right pulmonary artery compared with the left pulmonary artery (404 ± 16 versus 199 ± 71 tubules/mm2, respectively; p < 0.05). Conclusions These findings demonstrate that PAVMs developed in a clinically relevant animal model of SCPC concomitantly with differential changes in PAEC proliferative ability and phenotype. Moreover, there was a significant increase in the angiopoietin/Tie-2 complex in the right lung, which may provide novel therapeutic targets to attenuate PAVM formation after a SCPC.

Original languageEnglish
Pages (from-to)1442-1449
Number of pages8
JournalAnnals of Thoracic Surgery
Volume96
Issue number4
DOIs
StatePublished - Oct 2013

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