5-FU–induced regression of hemangiogenesis in wild-type mice. (A-B) Chemotherapy-mediated disruption of the BM vascular niche is followed by regeneration of neovessels. On days 4, 7, 10, 14, and 24 after injection, 3 mice were killed, and their femurs were collected and processed for histologic analysis. Paraffin sections of the BM were stained by H&E. Representative sections at steady state and after 4, 7, 10, 14, and 21 days are shown. Arrows point to the BM vascular sinusoids. At baseline, there are small and narrow sinusoids, decorated by hematopoietic cells (yellow arrows). On day 4, there is a complete disruption of vasculature with plasma leakage (red arrows). On day 7, marrow hypocellularity and regression of BM vasculature with areas of hemorrhage are readily evident (blue arrows). Simultaneous with the regeneration of BM vasculature, which manifests itself in the formation of early, dilated nascent neosinusoids (light blue arrows), there is a rapid increase in the platelet counts. By day 14, the newly reconstructed sinusoids undergo remodeling (green arrows), a process that is completed by day 24 after myelosuppression (orange arrows). (C) Recovery of hematopoiesis parallels the histologic changes observed after myelosuppression. Wild-type mice were intravenously injected with one single dose of 250 mg/kg 5-FU (n = 16). Complete blood counts, including a differential white-blood-cell (WBC) count, were obtained using the Advia 120 Multi-Species Hematology Analyzer after a single intravenous injection with 5-FU. (Left) After initial pancytopenia, there is a rebound thrombocytosis up to 3.0 × 106/μL that lasts for several days (n = 16, P < .01 at day 14, 250 mg/kg 5-FU) before platelet counts revert to normal levels around 4 weeks after injection. (Right) Similarly, white blood cells reach their nadir around day 7 to revert more slowly to normal 4 weeks after myelosuppression without displaying rebound leukocytosis. Polymorphonuclear neutrophils (PMNs) take the same course as total white blood cells with neutropenia lasting about 18 days (average ± SE).
