Complement Involvement in Neovascular Ocular 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 subreti-nal neovascularization from age-related macular degenera-tion or the presumed ocular histoplasmosis syndrome or retinal neovascularization from proliferative diabetic retinop-athy (PDR). Only rv13 was observed on blood vessels in ocular tissues with active neovascularization from patients with age-related macular degeneration or presumed ocular his-toplasmosis, 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 sub-retinal 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 age-related 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 proto-typic diseases for choroidal and retinal neovascularization, respectively, other conditions can selectively cause angiogen-esis 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 neovasculariza-tion (4-6), very little is known about the mechanism underlying vasoproliferation in these neovascular eye diseases.

AAV-mediated expression of human PRELP inhibits complement activation, choroidal neovascularization and deposition of membrane attack complex in mice

“…Despite this, we were surprised to find that instead of inhibiting the formation of tubes by HUVECs, PRELP enhanced tube formation more than two fold. This observation could be explained by considering that the complement cascade plays a significant role in angiogenesis in vivo 33 but in the HUVEC tube formation assay in vitro , the complement cascade is largely absent and hence angiogenesis in the in vitro model is primarily driven by factors other than complement, such as cytokines. This hypothesis is also consistent with the knowledge that the extracellular matrix also plays a key role in angiognenesis in vivo 34 and cells in culture have a limited extracellular matrix relative to that in vivo .…”

Inhibition of the alternative complement pathway preserves photoreceptors after retinal injury

“…Soluble and cell-bound regulators of complement (for example, Crry/CD46, CD55, and CD59) help to protect healthy host tissue from self-recognition and serve to prevent activation of a complement response (17, 26, 27). However, damaged or diseased host cells have been shown to down-regulate membrane-bound inhibitors of complement, allowing for targeted clearance (17, 28, 29). An imbalance between complement recognition and initiation on healthy host cells can lead to unregulated complement activation, opsonization, and/or subsequent cellular damage (17).…”

Rabdosia japonicavar.glaucocalyxFlavonoids Fraction Attenuates Lipopolysaccharide-Induced Acute Lung Injury in Mice

“…The complement system consists of more than 30 serum and cellular proteins, including positive and negative regulators, linked in three biochemical cascades, the classical, alternative and lectin complement pathways [42, 43]. C3 activation leads to the entry of the final common pathway resulting in the formation of the membrane attack complex (MAC, C5b-9) [44]. Animal model of ALI studies demonstrated alterations of complement 3 levels in ALI [5].…”