Pulmonary Artery Endothelial Cell Phenotypic Alterations in a Large Animal Model of Pulmonary Arteriovenous Malformations After the Glenn Shunt
Pulmonary Artery Endothelial Cell Phenotypic Alterations in a Large Animal Model of Pulmonary Arteriovenous Malformations After the Glenn Shunt
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DOI：
10.1016/j.athoracsur.2013.05.075
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发表时间：
2013-10-01
影响因子：
4.6
通讯作者：
Jones, Jeffrey A.
中科院分区：
文献类型：
--
作者：
Kavarana, Minoo N.;Mukherjee, Rupak;Jones, Jeffrey A.
背景。上腔静脉肺动脉连接（SCPC）的寿命受到肺动静脉畸形（PAVM）的发展的限制。本研究的目的是确定肺动脉内皮细胞 (PAEC) 的表型变化是否随着 PAVM 的形成而发生有利于血管生成。在 5 头猪身上构建了上腔静脉与右肺动脉的连接。术后 6 至 8 周采集肺动脉，建立 PAEC 和平滑肌细胞培养物，以确定细胞增殖、基因表达和小管形成。测量肺组织中与血管生成相关的蛋白质的丰度。结果。超声心动图显示从右向左分流，与 PAVM 形成一致。虽然右肺动脉（分流侧）和左肺动脉（非分流侧）的平滑肌细胞增殖相似，但右侧 PAEC 增殖明显更高。与左肺动脉相比，右肺动脉 PAEC 中编码细胞信号蛋白的基因表达谱更高。右肺中 angiopoietin-1 和 Tie-2（血管生成素受体）的蛋白质丰度增加（均 p < 0.05）。与左肺动脉相比，右肺动脉内皮细胞的小管形成增加（分别为 404 +/- 16 与 199 +/- 71 管/mm(2)；p < 0.05）。结论。这些发现表明，PAVM 在临床相关的 SCPC 动物模型中发育，同时伴有 PAEC 增殖能力和表型的差异变化。此外，右肺中血管生成素/Tie-2复合物显着增加，这可能为减少 SCPC 后 PAVM 的形成提供新的治疗靶点。 (C) 2013 年，胸外科医师协会
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. (C) 2013 by The Society of Thoracic Surgeons