title: DEP induction of ROS in capillary-like endothelial tubes leads to VEGF-A expression.
abstract: 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 (Chao et al., 2011). 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 24h 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 "vascular permeability factor" (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.
authors.affiliation: Pharmacology and Toxicology, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Ming Wei
authors.initials: MW
authors.lastname: Chao
authors.forename: Iris P
authors.initials: IP
authors.lastname: Po
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Laumbach
authors.forename: John
authors.initials: J
authors.lastname: Koslosky
authors.forename: Keith
authors.initials: K
authors.lastname: Cooper
authors.forename: Marion K
authors.initials: MK
authors.lastname: Gordon
mesh_terms: D002196:Capillaries / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D017382:Reactive Oxygen Species / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics; D001335:Vehicle Emissions / Q000633:toxicity*
chemical_list: D017382:Reactive Oxygen Species; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D001335:Vehicle Emissions; D051547:Heme Oxygenase-1