Persistent Inflammation Subverts Thrombospondin-1–Induced Regulation of Retinal Angiogenesis and Is Driven by CCR2 Ligation

Neovascular retinal disease is a leading cause of blindness orchestrated by inflammatory responses. Although noninfectious uveoretinitis is mediated by CD4(+) T cells, in the persistent phase of disease, angiogenic responses are observed, along with degeneration of the retina. Full clinical manifestation relies on myeloid-derived cells, which are phenotypically distinct from, but potentially sharing common effector responses to age-related macular degeneration. To interrogate inflammation-mediated angiogenesis, we investigated experimental autoimmune uveoretinitis, an animal model for human uveitis. After the initial acute phase of severe inflammation, the retina sustains a persistent low-grade inflammation with tissue-infiltrating leukocytes for over 4 months. During this persistent phase, angiogenesis is observed as retinal neovascular membranes that arise from inflamed venules and postcapillary venules, increase in size as the disease progresses, and are associated with infiltrating arginase-1(+) macrophages. In the absence of thrombospondin-1, retinal neovascular membranes are markedly increased and are associated with arginase-1(-) CD68(+) macrophages, whereas deletion of the chemokine receptor CCR2 resulted in reduced retinal neovascular membranes in association with a predominant neutrophil infiltrate. CCR2 is important for macrophage recruitment to the retina in experimental autoimmune uveoretinitis and promotes chronicity in the form of a persistent angiogenesis response, which in turn is regulated by constitutive expression of angiogenic inhibitors like thrombospondin-1. This model offers a new platform to dissect the molecular and cellular pathology of inflammation-induced ocular angiogenesis.

Radiation retinopathy--clinical, histopathological, ultrastructural and experimental correlations

Clinical, pathological and experimental studies of radiation retinopathy confirm that the primary vascular event is endothelial cell loss and capillary closure. Pericytes are less susceptible, but typically atrophy as the capillaries become non-functional. The immediate effects of radiation reflect interphase and early mitotic death of injured endothelial cells, whereas later changes may be attributed to delayed mitotic death of compromised endothelial cells as they attempt division in the ordinary course of repair and replacement. Capillary occlusion leads to the formation of dilated capillary collaterals which may remain serviceable and competent for years. Microaneurysms develop in acellular and poorly supported capillaries, predominantly on the arterial side of the circulation and adjacent to regions of poorly perfused retina. Alterations in haemodynamics produce large telangiectatic-like channels which, typically develop a thick collagenous adventitia and may become fenestrated. Limited capillary regeneration occurs, usually evident as recanalisation of arterioles or venules by new capillaries. Vitreo-retinal neovascularisation may occur where retinal ischaemia is widespread. Radiation produces an exaggerated vasculopathy in patients with diabetes mellitus, and five month streptozotocin-induced diabetic rats develop a severe ischaemic retinopathy with vitreoretinal neovascularisation when exposed to 1500 cGy of radiation. Later photocoagulation is useful in containing or reversing microvascular incompetence and vasoproliferation in some patients with advanced radiation retinopathy.

Automated detection and measurement of isolated retinal arterioles by a combination of edge enhancement and cost analysis

Pressure myography studies have played a crucial role in our understanding of vascular physiology and pathophysiology. Such studies depend upon the reliable measurement of changes in the diameter of isolated vessel segments over time. Although several software packages are available to carry out such measurements on small arteries and veins, no such software exists to study smaller vessels (<50 µm in diameter). We provide here a new, freely available open-source algorithm, MyoTracker, to measure and track changes in the diameter of small isolated retinal arterioles. The program has been developed as an ImageJ plug-in and uses a combination of cost analysis and edge enhancement to detect the vessel walls. In tests performed on a dataset of 102 images, automatic measurements were found to be comparable to those of manual ones. The program was also able to track both fast and slow constrictions and dilations during intraluminal pressure changes and following application of several drugs. Variability in automated measurements during analysis of videos and processing times were also investigated and are reported. MyoTracker is a new software to assist during pressure myography experiments on small isolated retinal arterioles. It provides fast and accurate measurements with low levels of noise and works with both individual images and videos. Although the program was developed to work with small arterioles, it is also capable of tracking the walls of other types of microvessels, including venules and capillaries. It also works well with larger arteries, and therefore may provide an alternative to other packages developed for larger vessels when its features are considered advantageous.

Retinal Vascular Caliber, Iris Color, and Age-Related Macular Degeneration in the Irish Nun Eye Study

Pupose. To evaluate the relationship between retinal vascular caliber (RVC), iris color and age-related macular degeneration (AMD) in elderly Irish nuns. Methods. Data from 1233 participants in the cross-sectional observational Irish Nun Eye Study were assessed from digital photographs with a standardized protocol using computer-assisted software. Macular images were graded according to the modified Wisconsin age-related maculopathy grading system. Regression models were used to assess associations, adjusting for age, mean arterial blood pressure, body mass index, refraction and fellow RVC. Results. In total, 1122 (91%) participants had gradable retinal images of sufficient quality for vessel assessment (mean age: 76.3 years [range: 56-100 years]). In an unadjusted analysis, we found some support for a previous finding that individuals with blue iris color had narrower retinal venules compared to those with brown iris color (P<0.05) but this was no longer significant after adjustment. AMD status was categorized as no AMD, any AMD and late AMD only. Individuals with any AMD (early or late AMD) had significantly narrower arterioles and venules compared to those with no AMD in an unadjusted analysis but this was no longer significant after adjustment. A non-significant reduced risk of any AMD or late AMD only was observed in association with brown compared to blue iris color, in both unadjusted and adjusted analyses. Conclusions. RVC was not significantly associated with iris color or early/late AMD after adjustment for confounders. A lower but non-significant AMD risk was observed in those with brown compared to blue iris color.

Increasing fruit and vegetable intake has no effect on retinal vessel caliber in adults at high risk of developing cardiovascular disease

BACKGROUND AND AIM: Retinal vessel abnormalities are associated with cardiovascular disease (CVD) risk. To date, there are no trials investigating the effect of dietary factors on the retinal microvasculature. This study examined the dose response effect of fruit and vegetable (FV) intake on retinal vessel caliber in overweight adults at high CVD risk.

METHODS AND RESULTS: Following a 4 week washout period, participants were randomized to consume either 2 or 4 or 7 portions of FV daily for 12 weeks. Retinal vessel caliber was measured at baseline and post-intervention. A total of 62 participants completed the study. Self-reported FV intake indicated good compliance with the intervention, with serum concentrations of zeaxanthin and lutein increasing significantly across the groups in a dose-dependent manner (P for trend < 0.05). There were no significant changes in body composition, 24-h ambulatory blood pressure or fasting blood lipid profiles in response to the FV intervention. Increasing age was a significant determinant of wider retinal venules (P = 0.004) whereas baseline systolic blood pressure was a significant determinant of narrower retinal arterioles (P = 0.03). Overall, there was no evidence of any short-term dose-response effect of FV intake on retinal vessel caliber (CRAE (P = 0.92) or CRVE (P = 0.42)).

CONCLUSIONS: This study demonstrated no effect of increasing FV intake on retinal vessel caliber in overweight adults at high risk of developing primary CVD.