DEP induction of ROS in capillary-like endothelial tubes leads to VEGF-A expression

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• 作者：Ming Wei Chao^a ; Iris P. Po^a ; Robert J. Laumbach^b ; John Koslosky^c ; Keith Cooper^d ; Marion K. Gordon^a ; ^{magordon@eohsi.rutgers.edu}
• 关键词：DEPs ; diesel exhaust particles ; HUVEC ; human umbilical vein endothelial cells ; PM2.5 ; particulate matter with diameters equal to or less than 2.5  ; 渭m ; VE-Cad ; vascular endothelial cell cadherin ; ROS ; reactive oxygen species ; VEGF-A ; vascular endothel
• 刊名：Toxicology
• 出版年：2012
• 期刊代码：47_0300483x
• 类别：pha
• 出版时间：16 July, 2012
• 卷：297
• 期：1-3
• 页码：34-46
• 文件大小：1581 K

摘要

Inhalation of diesel exhaust particles (DEPs) is associated with pulmonary and cardiovascular disease. One contributor to pathogenesis is inhaled particles reaching and injuring the lung capillary endothelial cells, and possibly gaining access to the blood stream. Using in vitro capillary tubes as a simplified vascular model system for this process, it was previously shown that DEPs induce the redistribution of vascular endothelial cell-cadherin (VE-Cad) away from the plasma membrane to intracellular locations. This allowed DEPs into the cell cytoplasm and tube lumen, suggesting the tubes may have become permeable (). Here some of the mechanisms responsible for endothelial tube changes after DEP exposure were examined. The results demonstrate that endothelial tube cells mounted an oxidative stress response to DEP exposure. Hydrogen peroxide and oxidized proteins were detected after 24 h of exposure to DEPs. Particles induced relocalization of Nrf2 from the cytoplasm to the nucleus, upregulating the expression of the enzyme heme oxygenase-1 (HO-1). Surprisingly, vascular endothelial cell growth factor-A (VEGF-A), initially termed 鈥渧ascular permeability factor鈥?(VPF), was found to be up-regulated in response to the HO-1 expression induced by DEPs. Similar to DEPs, applied VEGF-A induced relocalization of VE-Cadherin from the cell membrane surface to an intracellular location, and relocalization of VE-cadherin was associated with permeability. These data suggest that the DEPs may induce or contribute to the permeability of capillary-like endothelial tube cells via induction of HO-1 and VEGF-A.