title: Exposure to ambient air fine particulate matter prevents VEGF-induced mobilization of endothelial progenitor cells from the bone marrow.
abstract: BACKGROUND
  Exposure to ambient fine particulate matter air pollution (PM(2.5); < 2.5 µm in aerodynamic diameter) induces endothelial dysfunction and increases the risk for cardiovascular disease. Endothelial progenitor cells (EPCs) contribute to postnatal endothelial repair and regeneration. In humans and mice, EPC levels are decreased upon exposure to elevated levels of PM(2.5).
  
  
  OBJECTIVE
  We examined the mechanism by which PM(2.5) exposure suppresses circulating levels of EPCs.
  
  
  METHODS
  Mice were exposed to HEPA-filtered air or concentrated ambient fine particulate matter (CAP, 30-100 µg/m³) from downtown Louisville (Kentucky) air, and progenitor cells from peripheral blood or bone marrow were analyzed by flow cytometry or by culture ex vivo.
  
  
  RESULTS
  Exposure of the mice to CAP (6 hr/day) for 4-30 days progressively decreased circulating levels of EPCs positive for both Flk-1 and Sca-1 (Flk-1(+)/Sca-1(+)) without affecting stem cells positive for Sca-1 alone (Sca-1(+)). After 9 days of exposure, a 7-day exposure-free period led to complete recovery of the circulating levels of Flk-1(+)/Sca-1(+) cells. CAP exposure decreased circulating levels of EPCs independent of apoptosis while simultaneously increasing Flk-1(+)/Sca-1(+) cells in the bone marrow. We observed no change in tissue deposition of these cells. CAP exposure suppressed vascular endothelial growth factor (VEGF)-induced Akt and endothelial nitric oxide synthase (eNOS) phosphorylation in the aorta, and it prevented VEGF/AMD3100-induced mobilization of Flk-1(+)/Sca-1(+) cells into the peripheral blood. Treatment with stem cell factor/AMD3100 led to a greater increase in circulating Flk-1(+)/Sca-1(+) cells in CAP-exposed mice than in mice breathing filtered air.
  
  
  CONCLUSIONS
  Exposure to PM(2.5) increases EPC levels in the bone marrow by preventing their mobilization to the peripheral blood via inhibition of signaling events triggered by VEGF-receptor stimulation that are upstream of c-kit activation. Suppression of EPC mobilization by PM(2.5) could induce deficits in vascular repair or regeneration.
authors.affiliation: Diabetes and Obesity Center, University of Louisville, Louisville, Kentucky 40202, USA.
authors.forename: Petra
authors.initials: P
authors.lastname: Haberzettl
authors.forename: Jongmin
authors.initials: J
authors.lastname: Lee
authors.forename: Dheeraj
authors.initials: D
authors.lastname: Duggineni
authors.forename: James
authors.initials: J
authors.lastname: McCracken
authors.forename: Duane
authors.initials: D
authors.lastname: Bolanowski
authors.forename: Timothy E
authors.initials: TE
authors.lastname: O'Toole
authors.forename: Aruni
authors.initials: A
authors.lastname: Bhatnagar
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Conklin
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000187:drug effects*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects*; D004781:Environmental Exposure; D005434:Flow Cytometry; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods; D006801:Humans; D007629:Kentucky; D051379:Mice; D052638:Particulate Matter / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D052638:Particulate Matter; D042461:Vascular Endothelial Growth Factor A