Ambient fine particulate matter (PM) is the key components for air pollution, and associated with significant mortality. The majority of the mortality following PM exposure is related to cardiovascular diseases. Endothelial progenitor cells (EPCs) are critical to maintaining the integrity and function of blood vessels with bone marrow as one of their main sources. PM exposure exhibits various deleterious effects on cardiovascular system, and significantly decreases the number and function of EPCs. However, the mechanism(s) for PM exposure- induced impairment of EPCs has not been fully understood. Recently, we observed that PM exposure significantly decreased the level of circulating EPCs s and the population of bone marrow stem cells (BMSCs) within the bone marrow in association with increased level of reactive oxygen species (ROS) formation in mice. When ROS production was blocked, PM-induced reduction of EPCs and BMSCs was effectively prevented. The present project was proposed to test the hypothesis that PM exposure reduces the number and function of EPCs through oxidative stress-mediated reduction of BMSC population in bone marrow with reduced generation of EPCs from BMSCs. There are two specific aims: 1): to determine the effect of PM exposure on BMSCs and their endothelial differentiation; and 2): to define the role of oxidative stress in mediating the effect of PM exposure on BMSCs and their differentiation into EPCs. We will demonstrate that PM exposure leads to a significant reduction in the number and function of BMSCs in the bone marrow. We will determine if the decrease in the number of BMSCs is due to increased apoptosis or decreased proliferation. We will also conduct experiments using bone marrow transplantation (BMT) with eGFP-positive BMSCs to determine if PM exposure impairs the differentiation of BMScs into EPCs that may contribute to decreased number and function of EPCs in the setting of PM exposure. To determine if PM exposure could produce a similar effect on BMSCs as chronic air pollution, the experiments will be repeated using mice exposed to air pollution for up to 6 months. We will test whether PM-induced ROS production causes decreased number and function of BMSCs by blocking ROS production using either antioxidant N-acetylcysteine or concomitant overexpression of an antioxidant enzyme network of human copper/zinc superoxide dismutase (SOD) 1, extracellular SOD3, and glutathione peroxidase with decreased ROS formation. We will also use BMT model with eGFP-BMSCs to determine if PM-induced oxidative stress plays a critical role in the differentiation of BMSCs into EPCs. Experiments will be conducted to evaluate the role of ROS in the population of BMSCs and their differentiation into EPCs in the mice exposed to air pollution for up to 6 months. The data from this study will provide important and novel information on the mechanisms for the development of cardiovascular diseases in patients with PM exposure and air pollution, and help explore new approaches to preventing and treating cardiovascular diseases related to PM exposure. 1

Public Health Relevance

Air pollution is a major challenge to public health. Ambient fine particulate matter (PM) is the key components for air pollution with significant adverse impact on human health. A recent Global Burden of Disease Study showed that PM exposure is associated with significant mortality with the majority to be related to cardiovascular diseases especially coronary artery disease and stroke. Endothelial progenitor cells (EPCs) originate mainly from the bone marrow stem cells, and play a critical role in maintaining the structural and functional integrity of blood vessels. The number and function of EPCs are markedly reduced after PM exposure. This study will use specific air pollution animal models to investigate how PM exposure disrupts the generation and function of EPCs from bone marrow stem cells, and contributes to cardiovascular disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES026200-05
Application #
9767135
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Reinlib, Leslie J
Project Start
2016-09-01
Project End
2021-08-31
Budget Start
2019-09-01
Budget End
2020-08-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Missouri-Columbia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
153890272
City
Columbia
State
MO
Country
United States
Zip Code
65211
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Wang, Hai; Agarwal, Pranay; Xiao, Yichao et al. (2017) A Nano-In-Micro System for Enhanced Stem Cell Therapy of Ischemic Diseases. ACS Cent Sci 3:875-885
Cui, Yuqi; Sun, Qinghua; Liu, Zhenguo (2016) Ambient particulate matter exposure and cardiovascular diseases: a focus on progenitor and stem cells. J Cell Mol Med 20:782-93
Cui, Yuqi; Jia, Fengpeng; He, Jianfeng et al. (2015) Ambient Fine Particulate Matter Suppresses In Vivo Proliferation of Bone Marrow Stem Cells through Reactive Oxygen Species Formation. PLoS One 10:e0127309
Cui, Yuqi; Xie, Xiaoyun; Jia, Fengpeng et al. (2015) Ambient fine particulate matter induces apoptosis of endothelial progenitor cells through reactive oxygen species formation. Cell Physiol Biochem 35:353-63