Exposure to Ambient Air Fine Particulate Matter Prevents VEGF-Induced Mobilization of Endothelial Progenitor Cells from the Bone Marrow

BACKGROUND: Exposure to ambient fine particulate matter air pollution (PM2.5; < 2.5 mu m in aerodynamic diameter) induces endothelial dysfunction and increases the risk for cardio-vascular disease. Endothelial progenitor cells (EPCs) contribute to post-natal endothelial repair and regeneration. In humans and mice, EPC levels are decreased upon exposure to elevated levels of PM2.5. OBJECTIVE: We examined the mechanism by which PM2.5 exposure suppresses circulating levels of EPCs. METHODS: Mice were exposed to HEPA-filtered air or concentrated ambient fine particulate matter (CAP, 30-100 mu g/m(3)) 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. CONCLUSION: Exposure to PM2.5 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 PM2.5 could induce deficits in vascular repair or regeneration.