Abstract
Abstract: :
Purpose: Aging is independently associated with more severe pathology in many vascular beds. We have demonstrated that aged mice develop much more severe CNV than do young mice. Recently, we have discovered that 20% of the cellular components of CNV are derived from bone marrow–derived circulating vascular progenitor cells, which differentiate into mature endothelial cells (EC) or vascular smooth muscle cells (VSMC) in situ. We postulate that increased severity of CNV in old mice is mediated by EC or VSMC that differentiate from dysfunctional aged progenitors. If true, then bone marrow transplantation of old bone marrow into young mice should transfer increased severity of CNV. Methods: Chimeric GFP mice were generated by reconstituting C57/BL/6 mice with bone marrow from GFP transgenic mice. Laser induced CNV was induced one month after bone marrow transplant. Immunofluorescence staining was used to examine cross–sections and flatmount preparations of the choroid associated with CNV for macrophages (F4/80), VSMC (alpha smooth muscle actin), and EC (PECAM). Results: Young mice receiving young marrow (Y◊Y) demonstrated small CNV (1.4 ± 0.4 disc areas) and old mice receiving old marrow (O◊O) demonstrated large CNV (3.4 ± 1.1 disc areas), the same pattern observed previously in nontransplanted mice. However, young mice receiving old marrow also demonstrated large lesions (2.6 ± 0.7 disc areas, p<0.002 versus Y◊Y). 85% of the individual CNV lesions were large after O◊O mice compared to 14% large CNV in Y◊Y mice. 69% of lesions were large in O◊Y mice. The proportion of marrow–derived VSMC, but not EC, was dramatically increased in O◊Y mice versus Y◊Y mice. Conclusions: These data demonstrate that bone marrow from old mice transfers increased CNV severity into young mice, suggesting that old progenitors may acquire abnormalities in function that cause them to differentiate into pathological adult tissues. The data also suggest that mesenchymal progenitors and vascular smooth muscle cells, rather than endothelial progenitors, may be more important in regulating lesion severity.
Keywords: choroid: neovascularization • age–related macular degeneration • aging