Chronic exposure to trivalent arsenic (As III) is well known to cause cardiovascular diseases. In the human liver, As (III) promotes vascular remodeling, portal fibrosis, and hypertension, but the molecular pathophysiology of these As III-induced vascular changes is unknown. In general, the pathogenesis of As III induced vascular diseases has been understudied, in part, due to a lack of relevant animal models sensitive to chronic low dose As III effects. Our preliminary results show that exposure of intact adult mice to as low as 10 ppb of As III in their drinking water caused defenestration and capillarization of liver sinusoidal endothelium (LSEC). Furthermore, we also show that primary, short term cultures of murine or human LSEC are useful in revealing functional roles for As (III)-stimulated NADPH oxidase (NOX) generation of reactive oxygen species in the early signaling events affecting phenotype (e.g. fenestration) of this important target cell. The objective of the proposed studies is to use these in vivo and ex vivo models to investigate the mechanisms through which As (III) initiates LSEC remodeling and the molecular pathology of As (III)-induced vascular diseases. The global hypothesis for these studies states that As (III) acts at the level of g-protein coupled cell signaling to promote NOX oxidant generation that disrupts maintenance of LSEC fenestrations and suppression of capillarization. Accordingly, the specific aims of this proposal are to determine: I. the molecular mechanism by which As (III) causes liver sinusoidal capillarization and remodeling in intact mice. Wildtype and NOX deficient (p47phox -/-) mice will be exposed to As (III) (10-50 ppb) for 2 weeks and morphometric (light and electron microscopic level) determinants of SEC defenestration and capillarization will be quantified. Pharmacologically (antibodies to vascular endothelial cell growth factor receptor or Pertussis toxin) modified mice will be used to assess the contribution VEGF receptor and Gi-protein linked signaling to As III-induced vascular changes. II. the role of NOX generated superoxide in mediating As III-induced phenotypic conversion of primary murine and human LSEC. LSEC isolated from human liver or wildtype and p47phox -/- mice will be exposed to As (III) ex vivo to demonstrate mechanisms through which an imbalance of reactive oxygen and nitrogen species generation mediates AsIII-dysregulation of VEGF receptor maintained LSEC fenestration. III. if an imbalance in LSEC GT Pase activity mediates As (III) stimulated remodeling of the LSEC. Targeted delivery of RhoA or Rac1-GTPase siRNA and selective GT Pase activity assays will be used to dissect the roles of Rho family members in As (III)-stimulated LSEC capillarization.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES013781-03
Application #
7746410
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Nadadur, Srikanth
Project Start
2007-12-14
Project End
2012-11-30
Budget Start
2009-12-01
Budget End
2010-11-30
Support Year
3
Fiscal Year
2010
Total Cost
$332,161
Indirect Cost
Name
University of Pittsburgh
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Beezhold, Kevin; Klei, Linda R; Barchowsky, Aaron (2017) Regulation of cyclin D1 by arsenic and microRNA inhibits adipogenesis. Toxicol Lett 265:147-155
(2016) Erratum to: Arsenic Promotes NF-?b-Mediated Fibroblast Dysfunction and Matrix Remodeling to Impair Muscle Stem Cell Function. Stem Cells 34:2448
Zhang, Changqing; Ferrari, Ricardo; Beezhold, Kevin et al. (2016) Arsenic Promotes NF-?b-Mediated Fibroblast Dysfunction and Matrix Remodeling to Impair Muscle Stem Cell Function. Stem Cells 34:732-42
Dheer, Rishu; Patterson, Jena; Dudash, Mark et al. (2015) Arsenic induces structural and compositional colonic microbiome change and promotes host nitrogen and amino acid metabolism. Toxicol Appl Pharmacol 289:397-408
Ambrosio, Fabrisia; Brown, Elke; Stolz, Donna et al. (2014) Arsenic induces sustained impairment of skeletal muscle and muscle progenitor cell ultrastructure and bioenergetics. Free Radic Biol Med 74:64-73
Oberoi, Shilpi; Barchowsky, Aaron; Wu, Felicia (2014) The global burden of disease for skin, lung, and bladder cancer caused by arsenic in food. Cancer Epidemiol Biomarkers Prev 23:1187-94
Klei, Linda R; Garciafigueroa, D Yesica; Barchowsky, Aaron (2013) Arsenic activates endothelin-1 Gi protein-coupled receptor signaling to inhibit stem cell differentiation in adipogenesis. Toxicol Sci 131:512-20
Garciafigueroa, D Yesica; Klei, Linda R; Ambrosio, Fabrisia et al. (2013) Arsenic-stimulated lipolysis and adipose remodeling is mediated by G-protein-coupled receptors. Toxicol Sci 134:335-44
States, J Christopher; Barchowsky, Aaron; Cartwright, Iain L et al. (2011) Arsenic toxicology: translating between experimental models and human pathology. Environ Health Perspect 119:1356-63
Jang, An Soo; Concel, Vincent J; Bein, Kiflai et al. (2011) Endothelial dysfunction and claudin 5 regulation during acrolein-induced lung injury. Am J Respir Cell Mol Biol 44:483-90

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