Senescence regulates macrophage activation and angiogenic fate at sites of tissue injury in mice

Abstract

Abnormal angiogenesis plays a key role in diseases of aging such as heart disease, certain cancers, and eye diseases including age-related macular degeneration. Macrophages have been shown previously to be both anti-and proangiogenic, and their role in regulating angiogenesis at sites of tissue injury is critical and complex. In this study, we analyzed cytokine gene expression patterns of mouse macrophages by realtime quantitative PCR and tested the functional effects of senescence on gene expression and macrophage polarization. Following laser injury to the retina, IL-10 was upregulated and Fas ligand (FasL), IL-12, and TNF-α were downregulated in ocular macrophages of old mice (>18 months of age). Downregulation of FasL on macrophages led to a loss of the antiangiogenic phenotype, as evidenced by the inability of these macrophages to inhibit vascular endothelial cells. Our results demonstrate that senescence, FasL, and IL-10 are key determinants of macrophage function that alter the growth of abnormal postdevelopmental blood vessels in disease processes including blinding eye disease.

Single and Compound Knock-outs of MicroRNA (miRNA)-155 and Its Angiogenic Gene Target CCN1 in Mice Alter Vascular and Neovascular Growth in the Retina via Resident Microglia

“…Macrophages can exhibit both proand antiangiogenic functions based largely on their polarization by cytokines in the resident tissue microenvironment (71). Of these cytokines, IL-10 may possess the most significant influence on the polarization of macrophages and their ability to regulate angiogenesis in the eye (72). Low levels of IL-10, which is a characteristic feature of the retinal environment of miR-155 Ϫ/Ϫ mice after OIR, are associated with "classically activated" macrophage, or M1 macrophage, that displays an antiangiogenic phenotype.…”

Microglia and Monocyte-Derived Macrophages in Stroke

“…In contrast, peripheral macrophages exhibited less classical activation, leading to an attenuated proinflammatory response [207]. In a mouse model of age-related macular degeneration, ocular macrophages from old mice exhibited increased IL-10 but decreased IL-12 and TNF-α, suggesting that aged macrophages are polarized toward an M2-like phenotype [208]. Another study also reported increased numbers of M2 macrophages in the spleen, lymph nodes, and bone marrow of aged mice [209].…”

Endothelial cell FGF signaling is required for injury response but not for vascular homeostasis

“…To further investigate the role of EC FGFR1/2 in vascular response to injury, we examined vascular response to choroidal injury and retina hypoxia. Laser-induced choroidal neovascularization (CNV) is well described as a proliferative neovascular response to injury to the retinal pigment epithelium and Bruch's membrane underneath the retina and a murine surrogate for the wet form of age-related macular degeneration (33,34). Following choroidal injury, DCKO mice showed a marked reduction in CNV compared with control Flk1-Cre or Tie2-Cre and DFF mice, as determined by quantifying FITC-dextran-perfused neovascular complexes overlying the injury site (Fig.…”