Abstract 330: Mobilization Of Bone Marrow Progenitors By Ischemic Tissues Requires An Interplay Between Hematopoietic Cytokines And Placental Growth Factor (plgf)
It remains unclear how ischemic tissues stimulate the bone marrow (BM) to mobilize proangiogenic progenitors. We therefore ligated in wild type (WT) mice the femoral artery, and analyzed at several time points after ligation the levels of various angiogenic/hematopoietic cytokines and progenitor cell subpopulations in BM, peripheral blood and ischemic tissue (by ELISA, flow cytometry and cell culture assays). We found that, early after onset of limb ischemia, the blood plasma levels of hematopoietic (e.g. SDF-1, G-CSF, Tpo, Epo) but not angiogenic cytokines (e.g. PlGF, VEGF) were increased. Further studies revealed that these hematopoietic cytokines did not mobilize progenitors directly but, surprisingly, stimulated the expression of the angiogenic factor PlGF in the BM, resulting in at least two effects:
PlGF promotes the expansion of pro-angiogenic progenitors; and
PlGF determines the responsiveness of progenitors to stimuli.
In the later phase of ischemia, the levels of PlGF increased in plasma and ischemic muscle, and endothelial and myeloid progenitors were mobilized from the BM. Notably, both endothelial and myeloid progenitors expressed the PlGF receptor Flt-1. Consistent with this notion, mice lacking PlGF expanded and mobilized fewer progenitors after ischemia despite increased plasma levels of hematopoietic cytokines, resulting in impaired revascularization of the ischemic limb (as evidenced by histological and angiographic analysis of collateral vessels and neo-capillaries, perfusion studies as well as by functional exercise tests). By contrast, progenitor mobilization and revascularization of the ischemic limb were not affected in mice lacking VEGF-B (which also binds to Flt-1), suggesting that the vasculogenic and angiogenic response to ischemia only requires PlGF and Flt-1. Together, this study
unveils an unprecedented temporo-spatial alliance between hematopoietic and angiogenic factors in progenitor mobilization and revascularization following peripheral tissue ischemia;
further underscores the critical role of PlGF herein; and
is, to the best of our knowledge, the first to show the molecular mechanisms underlying the response of the BM compartment to peripheral ischemia.