Angiogenesis Associated with Other Pathological Conditions

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Diabetes mellitus, occlusion of central retinal vein, or prematurity, with subsequent exposure to oxygen, can all be associated with intraocular neovascularization (2). The new blood vessels may lead to vitreous hemorrhage, retinal detachment, neovascular glaucoma, and eventual blindness (2). Diabetic retinopathy is the leading cause of blindness in the working population (166). All of these conditions are known to be associated with retinal ischemia (167). In 1948, Michaelson (168) proposed that a key event in the pathogenesis of these conditions is the release by the ischemic retina into the vitreous diffusible angiogenic factor(s) (factor X) responsible for retinal and iris neovascularization. VEGF, by virtue of its diffusible nature and hypoxia inducibility, was an attractive candidate as a mediator of intraocular neovascularization. Accordingly, elevations of VEGF levels in the aqueous and vitreous humors of eyes with proliferative retinopathy have been described (169-171). In a large series, a strong correlation was found between levels of immunore-active VEGF in the aqueous and vitreous humors, and active proliferative retinopathy VEGF levels were undetectable or very low (<0.5 ng/mL) in the eyes of patients affected by nonneovascular disorders or diabetes without proliferative retinopathy (169). In contrast, the VEGF levels were in the range of 3-10 ng/mL in the presence of active proliferative retinopathy associated with diabetes, occlusion of central retinal vein, or prematurity.

More direct evidence for a role of VEGF as a mediator of intraocular neovascularization has been generated in a primate model of iris neovascularization, and in a murine model of retinopathy of prematurity (172,173). In the former, intraocular administration of anti-VEGF antibodies dramatically inhibits the neovascularization that follows occlusion of central retinal veins (174). Likewise, soluble Flt-1 or Flk-1 fused to an IgG suppresses retinal angiogenesis in the mouse model (175).

Neovascularization is a major cause of visual loss also in age-related macular degeneration (AMD), the overall leading cause of blindness (2). Most AMD patients have atrophy of the retinal pigment epithelial, and characteristic formations called "drusen." A significant percentage of AMD patients (~20%) manifest the neovascular (exuda tive) form of the disease. In this condition, the new vessels stem from the extraretinal choriocapillary (2). Leakage and bleeding from these vessels may lead to damage to the macula and ultimately to loss of central vision. Because of the proximity of the lesions to the macula, laser photocoagulation or surgical therapy are of very limited value. Very recent studies have documented the immunohistochemical localization of VEGF in surgically resected choroidal neovascular membranes from AMD patients (176,177). These findings suggest a role for VEGF in the progression of AMD-related choroidal neovascularization, raising the possibility that a pharmacological treatment with monoclonal antibodies or other VEGF inhibitors may constitute a therapy for this condition.

Two independent studies have suggested that VEGF is involved in the pathogenesis of rheumatoid arthritis (RA), an inflammatory disease in which angiogenesis plays a significant role (178,179). The RA synovium is characterized by the formation of pannus, an extensively vascularized tissue that invades and destroys the articular cartilage (180). Levels of immunoreactive VEGF were found to be high in the synovial fluid of RA patients; they were very low or undetectable in the synovial fluid of patients affected by other forms of arthritis, or by degenerative joint disease (178,179). Furthermore, anti-VEGF antibodies significantly reduced the endothelial cell chemotactic activity of the RA synovial fluid (178).

It has been shown that VEGF expression is increased in psoriatic skin (181). Increased vascularity and permeability are characteristic of psoriasis. Also, VEGF mRNA expression has been examined in three bullous disorders with subepidermal blister formation, bullous pemphigoid, erythema multiforme, and dermatitis herpetiformis (182).

Angiogenesis is also important in the pathogenesis of endometriosis, a condition characterized by ectopic endometrium implants in the peritoneal cavity. Recently, elevation of VEGF in the peritoneal fluid of patients with endometriosis have been reported (183,184). Immunohistochemistry indicated that activated peritoneal fluid macrophages as well as tissue macrophages within the ectopic endometrium are the main source of VEGF in this condition (183,184). VEGF upregulation has been also implicated in the hypervascularity of the ovarian stroma that characterizes Stein-Leventhal syndrome (185).

Moreover, Sato et al. (186) proposed that VEGF may be responsible for the characteristic hypervascularity of Graves' disease. TSH, insulin phorbol ester, dibutiryl cAMP, and Graves' IgG were found to stimulate VEGF mRNA expression in cultured human thyroid follicles (186).

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