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Background: Demyelinating polyneuropathy is a debilitating, poorly understood disease that can exist in acute (Guillain- Barré syndrome) or chronic forms. Interleukin-10 (IL-10), although traditionally considered an anti-inflammatory cytokine, has also been implicated in promoting abnormal angiogenesis in the eye and in the pathobiology of autoimmune diseases such as lupus and encephalomyelitis. Principal Findings: Overexpression of IL-10 in a transgenic mouse model leads to macrophage-mediated demyelinating polyneuropathy. IL-10 upregulates ICAM-1 within neural tissues, promoting massive macrophage influx, inflammationinduced demyelination, and subsequent loss of neural tissue resulting in muscle weakness and paralysis. The primary insult is to perineural myelin followed by secondary axonal loss. Infiltrating macrophages within the peripheral nerves demonstrate a highly pro-inflammatory signature. Macrophages are central players in the pathophysiology, as in vivo depletion of macrophages using clodronate liposomes reverses the phenotype, including progressive nerve loss and paralysis. Macrophage-mediate demyelination is dependent on Fas-ligand (FasL)-mediated Schwann cell death. Significance: These findings mimic the human disease chronic idiopathic demyelinating polyneuropathy (CIDP) and may also promote further understanding of the pathobiology of related conditions such as acute idiopathic demyelinating polyneuropathy (AIDP) or Guillain-Barré syndrome. [ABSTRACT FROM AUTHOR]

Aberrant angiogenesis in the eye is the most common cause of blindness. The current study examined the role of interleukin-10 (IL-10) in ischemia-induced pathological angiogenesis called neovascularization during postnatal development. IL-10 deficiency resulted in significantly reduced pathological retinal angiogenesis. In contrast to the choroicapillaris where IL-10 interferes with macrophage influx, IL-10 did not prevent anti-angiogenic macrophages from migrating to the retina in response to hypoxia. Instead, IL-10 promoted retinal angiogenesis by altering macrophage angiogenic function, as macrophages from wild-type mice demonstrated increased vascular endothelial growth factor (VEGF) and nitric oxide (NO) compared to IL-10 deficient macrophages. IL-10 appears to directly affect macrophage responsiveness to hypoxia, as macrophages responded to hypoxia with increased levels of IL-10 and STAT3 phosphorylation as opposed to IL-10 deficient macrophages. Also, IL-10 deficient macrophages inhibited the proliferation of vascular endothelial cells in response to hypoxia while wild-type macrophages failed to do so. These findings suggest that hypoxia guides macrophage behavior to a pro-angiogenic phenotype via IL-10 activated pathways. [ABSTRACT FROM AUTHOR]

Presents findings of a study which tested the effect of angiopoietin 2 (Ang2) on blood vessels. Impact of increased expression of Ang2 on mature retinal blood vessels; Contribution of Ang2 expression to stimulation of retinal neovascularization; Discussion on Ang2 inhibition of subretinal neovascularization in rho/vascular endothelial growth factor transgenic mice

Background: Age-related macular degeneration (AMD) is the leading cause of blindness in people over 50 y of age in at least three continents. Choroidal neovascularization (CNV) is the process by which abnormal blood vessels develop underneath the retina. CNV develops in 10% of patients with AMD but accounts for up to 90% of the blindness from AMD. Although the precise etiology of CNV in AMD remains unknown, the macrophage component of the inflammatory response, which has been shown to promote tumor growth and support atherosclerotic plaque formation, is thought to stimulate aberrant angiogenesis in blinding eye diseases. The current theory is that macrophage infiltration promotes the development of neovascularization in CNV.Methods and Findings: We examined the role of macrophages in a mouse model of CNV. IL-10(-/-) mice, which have increased inflammation in response to diverse stimuli, have significantly reduced CNV with increased macrophage infiltrates compared to wild type. Prevention of macrophage entry into the eye promoted neovascularization while direct injection of macrophages significantly inhibited CNV. Inhibition by macrophages was mediated by the TNF family death molecule Fas ligand (CD95-ligand).Conclusions: Immune vascular interactions can be highly complex. Normal macrophage function is critical in controlling pathologic neovascularization in the eye. IL-10 regulates macrophage activity in the eye and is an attractive therapeutic target in order to suppress or inhibit CNV in AMD that can otherwise lead to blindness. [ABSTRACT FROM AUTHOR]

The central role of vascular endothelial growth factor (VEGF) signaling in regulating normal vascular development and pathological angiogenesis has been documented in multiple studies. Ocular anti-VEGF therapy is highly effective for treating a subset of patients with blinding eye disorders such as diabetic retinopathy and neovascular age-related macular degeneration (AMD). However, chronic VEGF suppression can lead to adverse effects associated with poor visual outcomes due to the loss of prosurvival and neurotrophic capacities of VEGF. In this review, we discuss emerging evidence for immune-related mechanisms that regulate ocular angiogenesis in a VEGF-independent manner. These novel molecular and cellular pathways may provide potential therapeutic avenues for a multitarget strategy, preserving the neuroprotective functions of VEGF in those patients whose disease is unresponsive to VEGF neutralization. [ABSTRACT FROM AUTHOR]

Perturbations in WNT signaling are associated with congenital eye disorders, including familial exudative vitreoretinopathy and Norrie disease. More recently, activation of the WNT pathway has also been shown to be associated with age-related macular degeneration (AMD). In this study, we identified that in choroidal neovascular membranes from AMD patients, β-catenin is activated specifically in the vascular endothelium, suggesting that WNT promotes pathologic angiogenesis by directly affecting vascular endothelial cells. WNT7B has been shown to be important during eye development for regression of the fetal hyaloid vasculature. However, it has not yet been established whether WNT7A and/or WNT7B are involved in neovascular AMD pathogenesis. Here, we show that WNT7A and WNT7B increase the proliferation of human dermal microvascular endothelial cells in a dose-dependent manner. Both WNT7A and WNT7B also stimulated vascular sprouting from mouse choroidal explants in vitro . To evaluate in vivo relevance, we generated mice systemically deficient in Wnt7a and/or Wnt7b . Genetic deletion of both Wnt7a and Wnt7b decreased the severity of laser injury-induced choroidal neovascularization (CNV), while individual deletion of either Wnt7a or Wnt7b did not have a significant effect on CNV, suggesting that WNT7A and WNT7B have redundant pro-angiogenic roles in vivo . Cumulatively, these findings identify specific WNT isoforms that may play a pathologic role in CNV as observed in patients with neovascular AMD. Although the source of increased WNT7A and/or WNT7B in CNV requires further investigation, WNT signaling may be a potential target for therapeutic intervention if these results are demonstrated to be relevant in human disease. [ABSTRACT FROM AUTHOR]

Purpose: To define the role of intravitreal bevacizumab in individuals with choroidal neovascularization (CNV) resulting from Ocular Histoplasmosis syndrome (OHS). Design: Retrospective chart review of a surgical therapy. Methods: We reviewed the course of 28 eyes of 28 patients who underwent intravitreal injection of bevacizumab for treatment of CNV secondary to OHS. Outcome was measured by pretreatment and posttreatment visual acuity (VA). Results: The average pretreatment logarithm of the minimum angle of resolution (logMAR) VA was 0.65 (Snellen equivalent of 20/88). Mean follow-up was 22.43 weeks with an average of 1.8 intravitreal injections. Average final logMAR VA was 0.43 (Snellen equivalent of 20/54). Twenty eyes (71%) experienced an increase in central VA, whereas four eyes (14%) were unchanged and four eyes (14%) experienced a decrease in vision. Conclusions: Intravitreal bevacizumab may improve or stabilize VA in a significant majority of patients with neovascular complications of OHS (24 eyes [85.7%] in our study population). [Copyright &y& Elsevier]

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 real-time 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-alpha 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. [ABSTRACT FROM AUTHOR]