Abstract 1040: Effect of FGF2 in Statin-Mediated Vasculoprotection by Circulating Endothelial Progenitor Cells
Background Bone marrow (BM)-derived endothelial progenitor cells (EPC) contribute to endothelial cell repair of the vessel wall. Statins effectively mobilize EPC into peripheral blood, increase the clonogenic potential of progenitor cells, and enhance reendothelialization after focal endothelial cell damage. Fibroblast growth factor-2 (FGF2) is an important mitogenic and proangiogenic factor which regulates endothelial cell growth, migration, and reendothelialization. Here we determine the underlying molecular mechanisms in statin-mediated progenitor cell mobilization.
Methods and Results In order to evaluate the role of FGF in stem and progenitor cell mobilization, FGF2 knock-out (-/-) mice were treated with the HMG-CoA reductase-inhibitor rosuvastatin (10mg/kg body weight s.c. per day) and placebo. The number of Sca1/flk-1 positive EPC in peripheral blood and BM was determined using flow-cytometry. In contrast to wild-type mice with an identical genetic background, rosuvastatin treated FGF2-/-mice did not show a statin-induced progenitor cell mobilization apparently due to an accumulation of Sca1/flk-1 positive cells within the BM. To evaluate the functional effects of the abrogated EPC mobilization and potential effects of FGF2 at the vascular wall, we evaluated reendothelialization in a mouse model of a focal endothelial cell denudation. Rosuvastatin treatment significantly reduced neointima formation due to an enhanced reendothelialization process while a reduction in neointima formation was not present in FGF2-/- mice. In addition, we determined the ability to form neo-vessels in a subcutaneous disc model of inflammation. Compared to wild-type mice, FGF2-/- mice demonstrated a severe reduction in neoangiogenesis despite statin treatment.
Conclusion FGF2 plays a major role in the statin-mediated mobilization of stem and progenitor cells from the bone marrow into peripheral blood. The lack of mobilization in FGF2-/- mice is associated with an impaired reendothelialization process resulting in an enhanced neointima formation and with a diminished angiogenic capacity as demonstrated in a model of neoangiogenesis. FGF2-/- mice are an important model to study the molecular mechanisms of EPC mobilization.