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Kaylee Smith, Alexandra Castillejos, Daniel Diaz-Aguilar, Clifford Kim, Harry Sweigard, Kip M Connor; The role of the alternative complement pathway in vascular regression. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3406.
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Abnormal blood vessel growth in the retina can impair vision and lead to blindness. Several forms of retinal disease, such as diabetic retinopathy, exhibit this phenomenon of neovascularization, which often progresses in two distinct phases: initial vascular regression (Phase-I) and subsequent pathological NV (Phase-II). Recent studies have identified a link between the complement system, a proteolytic cascade of the innate-immune system, and the extent of NV induced during phase-II of retinopathy. However, the identification of immune-factors producing regression in phase-I remains to be determined.
Following an oxygen induced retinopathy model, postnatal day 7 WT mice were exposed to 75% oxygen for 24 hours. Using laser capture microdissection, we evaluated the changes in complement factor transcription in these mice (n=6) versus age- and strain-matched mice kept at room oxygen (n=6). Transcription levels of membrane-bound complement inhibitors: Cd55 and Cd59, and soluble complement factors: C3, C5, and alternative-specific factor B (Fb) were measured in the retinal vasculature, retinal pigment epithelium (RPE), outer nuclear layer (ONL), inner nuclear layer (INL) and ganglion cell layer (GCL).
Retinal vasculature analysis revealed that alternative pathway-deficient (Fb-/-) mice (n=10) exhibited less vaso-obliteration than strain-matched WT mice (n=8) (p<0.05). The RPE and ONL were identified to be a major site of Fb translation and demonstrated increased expression following hyperoxia (p<0.01). The ONL was also identified as a major production site for C3 and C5, (p<0.05). Within retinal vasculature, transcription of both complement inhibitors was decreased (p<0.001).
Our results implicate the alternative pathway as a mediator of vascular regression during phase-I of retinopathy. Specifically, upstream complement factors are induced in the retina, while the targeted removal of vessels is achieved by down-regulating their expression of complement inhibitors. To our knowledge, this is the first study to identify locations and relative expression of retinal complement factor transcription during retinopathy.
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