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Development of a Novel Assay to Test Environmental Contaminates on Vascular Growth, Differentiation, and StabilizationEPA Grant Number: F5D40867
Title: Development of a Novel Assay to Test Environmental Contaminates on Vascular Growth, Differentiation, and Stabilization
Investigators: Straub, Adam C.
Institution: University of Pittsburgh - Main Campus
EPA Project Officer: Jones, Brandon
Project Period: August 29, 2005 through August 29, 2008
Project Amount: $111,172
RFA: STAR Graduate Fellowships (2005) RFA Text | Recipients Lists
Research Category: Academic Fellowships
Elevated levels of arsenic in the drinking water affects the health of over 50 million people worldwide by increasing the risk of cardiovascular diseases and cancer. Vascular remodeling, thickening of blood vessel walls, and vascular occlusions are common findings in cardiovascular diseases associated with chronic ingestion of low levels of arsenic. There are strong epidemiologic associations between arsenic and ischemic diseases, but little is known about the basic mechanisms and signaling events that mediate the cardiovascular toxicity of arsenic. More recently, roxarsone, a derivative of arsenic became a concern due to the fact that feeding this arsenical to millions of boilers and pigs yearly has been shown to increase levels of environmental arsenic contamination. Therefore our proposed studies will build on novel reports of arsenic effects on vascular cell signal transduction, phenotypic change, and neovascularization. The global hypothesis for the proposed studies is that arsenicals induce chronic phenotypic change associated with pathological neovascualarization by selectively stimulating proliferative signals in vascular cells. A secondary objective is to prove the utility of the mouse embryoid body (EB) model for identifying the vascular toxicity of environmental compounds.Approach:
The proposed studies have several goals. First, we have adapted a model using mouse embryonic stem cells under a vascular development program in a 3 dimensional Matrigel matrix. This model allows us to investigate the mechanisms for the effects of AsIII on neovascularization. More importantly this model allows for further investigation of AsIII effects on proliferation, differentiation of endothelial progenitor cells and their transdifferentiation into SMC. The mouse embryonic stem cell model has a distinct advantage over single cell cultures in that the full neovascularization program can be analyzed in the context of appropriate cell-to-cell communication. In addition to being able to identify genomic and proteomic effects of AsIII on the developing vasculature and vessel remodeling, the EB model is easy to modify genetically for mechanistic studies. We will also use the mouse EB model to study the effects of roxarsone and how it may possibly contribute a pathological neovascularization process.Rationale:
Arsenic is an environmental contaminant found in drinking water that affects the health over 50 million people worldwide. Individuals who consume elevated levels of arsenic in their drinking water have an increased risk of developing cardiovascular disease through unknown causes. Therefore, the proposed studies will define how consumption of environmental arsenic changes the behavior of blood vessel cells to promote blockage or loss of blood flow. The knowledge gained will greatly aid development of policies and strategies to prevent or treat arsenic related vascular disease.Expected Results:
The proposed studies should establish conditions for using the mouse EB model to study the vascular remodeling effects of environmental contaminants including arsenic and roxarsone. More importantly, this model will be used to define signaling mechanisms by which AsIII and other arsenicals promote the neovascularization process.
Underlying mechanisms that drive arsenic-induced vascular disease is of importance in defining its etiology. Advancement in our understanding of these mechanisms may greatly aid in the development of strategies to prevent or treat arsenic-induced vascular diseases.Supplemental Keywords:
Arsenic, angiogenesis, vasculogenesis, cardiovascular disease, roxarsone, embryonic stem cells, embryoid bodies, EB model, endothelial cells, smooth muscle cells, water, toxicology, transdifferentiation, environment,, RFA, Health, Scientific Discipline, Water, POLLUTANTS/TOXICS, Health Risk Assessment, Arsenic, Risk Assessments, Biochemistry, Water Pollutants, Biology, chemical exposure, toxicology, drinking water, animal model, disease potential, carcinogens, vascular dysfunction, toxicologic assessment, cardiotoxicity, cardiovascular disease