Involvement of integrins alpha v beta 3 and alpha v beta 5 in ocular neovascular diseases.

Abstract

Angiogenesis underlies the majority of eye diseases that result in catastrophic loss of vision. Recent evidence has implicated the integrins r4P3 and Cv435 in the angiogenic process. We examined the expression of C4133 and CX485 in neovascular ocular tissue from patients with subretinal neovascularization from age-related macular degeneration or the presumed ocular histoplasmosis syndrome or retinal neovascularization from proliferative diabetic retinopathy (PDR). Only rv13 was observed on blood vessels in ocular tissues with active neovascularization from patients with age-related macular degeneration or presumed ocular histoplasmosis, whereas both aP3 and aP5 were present on vascular cells in tissues from patients with PDR Since we observed both integrins on vascular cells from tissues of patients with retinal neovascularization from PDR, we examined the effects of a systemically administered cyclic peptide antagonist of aM83 and C4185 on retinal angiogenesis in a murine model. This antagonist specifically blocked new blood vessel formation with no effect on established vessels. These results not only reinforce the concept that retinal and subretinal neovascular diseases are distinct pathological processes, but that antagonists of a433 and/or aC45 may be effective in treating individuals with blinding eye disease associated with angiogenesis.The pathological growth of new blood vessels underlies most eye diseases that cause catastrophic loss of vision. The leading cause of blindness in individuals over the age of 55 is agerelated macular degeneration (ARMD); under 55 years of age, the leading cause is proliferative diabetic retinopathy (PDR) (1). The two diseases are further distinguished by the specific site of new blood vessel growth; ARMD is characterized by choroidal neovascularization (2), whereas in PDR retinal blood vessels proliferate along the surface of the retina and into the posterior vitreous (3). [The posterior eye has a dual blood supply consisting of (i) the retinal blood vessels that branch from the central retinal artery and supply the inner one-third of the retina and (ii) the choroid that forms an extensive subretinal vascular plexus and nourishes the outer two-thirds of the retina.] While ARMD and PDR are prototypic diseases for choroidal and retinal neovascularization, respectively, other conditions can selectively cause angiogenesis of either vasculature. In general, diseases of a degenerative (e.g., ARMD, pathological myopia) or inflammatory [e.g., presumed ocular histoplasmosis syndrome (POHS)] nature manifest as choroidal neovascularization, whereas ischemic diseases (e.g., PDR, retinopathy of prematurity, sickle cell retinopathy) result in retinal angiogenesis. Although a number of recent studies have demonstrated an association between elevated intraocular levels of vascular endothelial growth factor (VEGF) and ischemia-related retinal neovascularization (4-6), very little is known about the mechanism underlying vasoproliferation in these neovascular eye diseases.

Diabetes enhances the efficacy of AAV2 vectors in the retina: therapeutic effect of AAV2 encoding vasoinhibin and soluble VEGF receptor 1

“…High glucose levels upregulate cell-associated proteoglycans in retinal pericytes 58 and promote the secretion of HS chains by endothelial cells, 59 and VEGF increases the retinal expression of the HS side chains of HSPGs. 60 Perlecan binds FGFs, 61,62 and the intraretinal stores of immunoreactive bFGF and HSPG increase in patients with DR. 63 Of note, abnormal HSPG expression and structure can contribute to vascular leakage and to the release of pro-angiogenic factors in DR, 64 whereas bFGF, αvβ5 integrin, and HGF can signal to promote angiogenesis in DR. 65 However, contrary to what is expected from our findings using rats after 6 weeks of STZ, the mRNA levels of perlecan, the [ 35 S] sulfate incorporation into HSPG, 66 and the immunolocalization of HSPG 67 decrease in the retina of diabetic rats at 5 and 11 months after STZ treatment, respectively. These findings suggest that the synthesis of HSPG may change as diabetes progresses and emphasize the need to examine the long-term differential efficacy of AAV2 vectors.…”

Pharmacoproteomic Analysis of a Novel Cell-permeable Peptide Inhibitor of Tumor-induced Angiogenesis

“…Several growth factors including FGF2 and tumor necrosis factor-␣ increase ␣ v ␤ 3 expression in the developing blood vessels of chick embryo (11) and rabbit cornea (5). ␣ v ␤ 3 expression is also stimulated by human tumors cultured on chick chorioallantoic membrane, rabbit cornea, and SCID mice (12). Antagonists of ␣ v ␤ 3 , including Arg-Gly-Asp(RGD)-containing disintegrins, cyclic RGD peptides, and monoclonal antibodies, significantly suppress cytokine-and solid tumor fragment-stimulated angiogenesis in proliferating vascular endothelial cells by inducing apoptosis (11,6).…”

Embryonic Fibroblasts That Are Genetically Deficient in Low Density Lipoprotein Receptor-related Protein Demonstrate Increased Activity of the Urokinase Receptor System and Accelerated Migration on Vitronectin

“…Integrins have been strongly implicated in cellular migration (1,2,5). For example, expression of ␣ v ␤ 3 is correlated with angiogenesis and migration of vascular smooth muscle cells (8,9). Embryonic stem cells that are ␤ 1 -deficient fail to migrate (10), and the absence of ␤ 2 subunits in the disease, leukocyte adhesion deficiency syndrome, results in defective migration of neutrophils across the endothelium and into the tissue spaces (11).…”