Sox18 preserves the pulmonary endothelial barrier under conditions of increased shear stress.
Sox18 preserves the pulmonary endothelial barrier under conditions of increased shear stress.
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DOI：
10.1002/jcp.24633
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发表时间：
2014-11
影响因子：
5.6
通讯作者：
Black, Stephen M.
中科院分区：
文献类型：
--
作者：
Gross, Christine M.;Aggarwal, Saurabh;Kumar, Sanjiv;Tian, Jing;Kasa, Anita;Bogatcheva, Natalia;Datar, Sanjeev A.;Verin, Alexander D.;Fineman, Jeffrey R.;Black, Stephen M.
在一些出生时患有先天性心脏畸形的儿童中，继发于肺血流量(PBF)增加的剪应力是升高的。然而，尽管存在高水平的通透性诱导因素，这些患者中的大多数都不会发展为肺水肿。以往的研究表明，层流剪切应力可以增强肺血管屏障的完整性。然而，人们对这种情况发生的机制知之甚少。利用基因芯片分析，我们先前已经证明，参与血管发育和内皮屏障完整性的转录因子Sox18在伴有PBF增加(分流)的绵羊模型中表达上调。通过使绵羊肺动脉内皮细胞(PAEC)承受层流(20dyn/cm2)，我们发现跨PAEC单层的跨内皮阻力(TER)增加，这与Sox18表达的增加有关。此外，当Sox18过度表达时，TER也被增强，而当Sox18表达降低时，TER则减弱，这表明Sox18维持了内皮屏障的完整性，以响应剪切力。此外，我们还发现，剪切力以一种依赖于Sox18的方式上调细胞紧密连接蛋白Claudin-5，并且Claudin-5的缺失取消了Sox18介导的TER的增加。最后，利用PBF增加的4周龄分流羔羊的外周肺组织，我们发现Sox18和Claudin-5的mRNA和蛋白水平都升高。总之，这些新的发现表明，增加的层流通过上调Sox18依赖的Claudin-5的表达来保护内皮屏障功能。
Shear stress secondary to increased pulmonary blood flow (PBF) is elevated in some children born with congenital cardiac abnormalities. However, the majority of these patients do not develop pulmonary edema, despite high levels of permeability inducing factors. Previous studies have suggested that laminar fluid shear stress can enhance pulmonary vascular barrier integrity. However, little is known about the mechanisms by which this occurs. Using microarray analysis, we have previously shown that Sox18, a transcription factor involved in blood vessel development and endothelial barrier integrity, is up-regulated in an ovine model of congenital heart disease with increased PBF (shunt). By subjecting ovine pulmonary arterial endothelial cells (PAEC) to laminar flow (20 dyn/cm2), we identified an increase in trans-endothelial resistance (TER) across the PAEC monolayer that correlated with an increase in Sox18 expression. Further, the TER was also enhanced when Sox18 was over-expressed and attenuated when Sox18 expression was reduced, suggesting that Sox18 maintains the endothelial barrier integrity in response to shear stress. Further, we found that shear stress up-regulates the cellular tight junction protein, Claudin-5, in a Sox18 dependent manner, and Claudin-5 depletion abolished the Sox18 mediated increase in TER in response to shear stress. Finally, utilizing peripheral lung tissue of 4 week old shunt lambs with increased PBF, we found that both Sox18 and Claudin-5 mRNA and protein levels were elevated. In conclusion, these novel findings suggest that increased laminar flow protects endothelial barrier function via Sox18 dependent up-regulation of Claudin-5 expression.
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发表时间：
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影响因子：
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作者：
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