title: Pulmonary artery endothelial cell phenotypic alterations in a large animal model of pulmonary arteriovenous malformations after the Glenn shunt.
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/mm(2), 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.
authors: Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, South Carolina. Electronic address: kavarana@musc.edu.
authors: Minoo N
authors: MN
authors: Kavarana
authors: Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, South Carolina.
authors: Rupak
authors: R
authors: Mukherjee
authors: Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, South Carolina.
authors: Shaina R
authors: SR
authors: Eckhouse
authors: Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, South Carolina.
authors: William F
authors: WF
authors: Rawls
authors: University of South Carolina School of Medicine, Columbia, South Carolina.
authors: Christina
authors: C
authors: Logdon
authors: Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, South Carolina.
authors: Robert E
authors: RE
authors: Stroud
authors: Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, South Carolina.
authors: Risha K
authors: RK
authors: Patel
authors: Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, South Carolina.
authors: Elizabeth K
authors: EK
authors: Nadeau
authors: University of South Carolina School of Medicine, Columbia, South Carolina.
authors: Francis G
authors: FG
authors: Spinale
authors: Division of Pediatric Cardiology, Medical University of South Carolina, Charleston, South Carolina.
authors: Eric M
authors: EM
authors: Graham
authors: Division of Pediatric Cardiology, Medical University of South Carolina, Charleston, South Carolina.
authors: Geoffrey A
authors: GA
authors: Forbus
authors: Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, South Carolina.
authors: Scott M
authors: SM
authors: Bradley
authors: Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, South Carolina.
authors: John S
authors: JS
authors: Ikonomidis
authors: Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, South Carolina; Division of Pediatric Cardiology, Medical University of South Carolina, Charleston, South Carolina.
authors: Jeffrey A
authors: JA
authors: Jones
mesh_terms: D000714:Anastomosis, Surgical; D000818:Animals; D001165:Arteriovenous Malformations / Q000235:genetics* / Q000473:pathology*; D004195:Disease Models, Animal; D042783:Endothelial Cells; D004730:Endothelium, Vascular / Q000166:cytology*; D005260:Female; D010641:Phenotype; D011651:Pulmonary Artery / Q000166:cytology*; D013552:Swine; D014656:Vascular Surgical Procedures / Q000379:methods
keywords: 21; AVM; Ct; EC; ECM; HIF; LPA; PA; PAEC; PAVM; RPA; SCPC; SMC; VEGF; arteriovenous malformations; cycle threshold; endothelial cell; extracellular matrix; hypoxia inducible factor; left pulmonary artery; pulmonary arteriovenous malformation; pulmonary artery; pulmonary artery endothelial cell; right pulmonary artery; smooth muscle cell; superior cavopulmonary connection; vascular endothelial growth factor
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