Lymphangiogenesis, an important initial step in tumor metastasis and transplant sensitization, is mediated by the action of VEGF-C and -D on VEGFR3. In contrast, VEGF-A binds VEGFR1 and VEGFR2 and is an essential hemangiogenic factor. We re-evaluated the potential role of VEGF-A in lymphangiogenesis using a novel model in which both lymphangiogenesis and hemangiogenesis are induced in the normally avascular cornea. Administration of VEGF Trap, a receptor-based fusion protein that binds and neutralizes VEGF-A but not VEGF-C or -D, completely inhibited both hemangiogenesis and the outgrowth of LYVE-1+ lymphatic vessels following injury. Furthermore, both lymphangiogenesis and hemangiogenesis were significantly reduced in mice transgenic for VEGF-A164/164 or VEGF-A188/188 (each of which expresses only one of the three principle VEGF-A isoforms). Because VEGF-A is chemotactic for macrophages and we demonstrate here that macrophages in inflamed corneas release lymphangiogenic VEGF-C/VEGF-D, we evaluated the possibility that macrophage recruitment plays a role in VEGF-A–mediated lymphangiogenesis. Either systemic depletion of all bone marrow–derived cells (by irradiation) or local depletion of macrophages in the cornea (using clodronate liposomes) prior to injury significantly inhibited both hemangiogenesis and lymphangiogenesis. We conclude that VEGF-A recruitment of monocytes/macrophages plays a crucial role in inducing inflammatory neovascularization by supplying/amplifying signals essential for pathological hemangiogenesis and lymphangiogenesis
There is concurrent, VEGF-A-dependent hem- and lymphangiogenesis after normal-risk keratoplasty within the preoperatively avascular recipient bed. Inhibition of hem- and lymphangiogenesis (afferent and efferent arm of an immune response) after normal-risk corneal transplantation improves long-term graft survival, establishing early postoperative hem- and lymphangiogenesis as novel risk factors for graft rejection even in low-risk eyes.
To measure the extent of choriocapillaris degeneration (CCD) in diabetic choroids and to study the association of CCD with choroidal neovascularization and pathologic changes in Bruch's membrane-like basal laminar deposits. Materials and Methods: Human choroids from 10 postmortem subjects (diabetic, 5 [group 1]; nondiabetic, 5 [group 2]) were incubated for the histochemical demonstration of alkaline phosphatase and nonspecific esterase activities, permitting analysis of the choroidal vasculature and polymorphonuclear leukocytes, respectively. The tissue was then flat embedded and sectioned for structural analysis. Areas of CCD were measured in the flat perspective by computer-assisted image analysis and verified in cross-sections of flat-embedded tissue. Results: The CCD in choroids from subjects with diabetes (group 1) appeared in 2 patterns: diffuse (partial loss of alkaline phosphatase activity in a poorly defined area, ie, degeneration of some capillary segments) and focal (complete degeneration of choriocapillaris or loss of alkaline phosphatase activity in a relatively welldefined area). The mean±SD percentage of the choroid with focal CCD in group 1 was 5.08%±1.13% of the total choroidal area vs 1.16%±0.35% in group 2 (PϽ.001). Focal CCD in group 1 was more prominent in the posterior pole than in the peripheral choroid. Choroidal neovascularization was associated with some areas of diffuse CCD in group 1. Pathologic changes in Bruch's membrane-like basal laminar deposits were often associated with CCD; the thickness of the deposits was greater in group 1 than in group 2 and greater in areas with focal CCD than in areas with diffuse or no CCD. Conclusion: The percentage of choroid with focal CCD in group 1 choroids was more than 4-fold greater than that in nondiabetic choroids. The presence of CCD was related to basal laminar deposits and, in some cases, to choroidal neovascularization.
The subretinal Matrigel CNV model provides a convenient tool for the study of the diverse components of complex CNV lesions. The data not only confirm the critical roles of VEGF in the development and maintenance of CNV, but further demonstrate that VEGF and other VEGF receptor 1 ligands promote CNV-associated inflammation and fibrosis.
A single intravitreal 200 ng dose of EPO appears to have a protective effect on RGC viability in an in vivo rat model of glaucoma. Further experimental studies are needed to confirm these preliminary results and to optimize the appropriate dose and frequency of EPO delivery in animal models of glaucoma.
Background/aims-Preretinal neovascular formations called sea fans develop at the border of non-perfused peripheral retina in sickle cell retinopathy. Angiogenic factors which could contribute to their development, however, have not been examined previously. The objective of this study was to determine immunohistochemically if vascular endothelial growth factor (VEGF) or basic fibroblast growth factor (bFGF) were associated with sea fan formations. Methods-Immunohistochemistry on cryosections was used to localise bFGF, VEGF, heparan sulphate proteoglycan, human serum albumin, collagens IV and II, and von Willebrand factor in tissue from five sickle cell and one control subject. Results-The greatest immunoreactivity for VEGF and bFGF was in the feeder and preretinal vessels of sea fans (p<0.01). The most prominent reaction product was localised to vascular endothelial cells. In retinal vessels, VEGF and bFGF immunoreactivities were greater in sickle cell subjects (both proliferative and nonproliferative) than in the control subject (p<0.01 and p<0.02 respectively). In the sickle cell retina, no angiogenic factor immunoreactivity was detected in nonperfused periphery and there was no significant diVerence in bFGF or VEGF immunoreactivity between perfused retina and the border of perfused and non-perfused areas. Conclusion-Our results demonstrate for the first time that VEGF and bFGF are associated with sea fan formations in sickle cell retinopathy. Both factors may function in an autocrine manner because immunoreactivity for these factors was greater within the neovascularisation than in adjacent retina. (Br J Ophthalmol 1999;83:838-846)
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