Pathological neovascularization is a hallmark of retinopathy of prematurity (ROP) and diabetic retinopathy (DR), where the balance between neovessel formation and regression determines disease severity. This proposal investigates a novel mechanism whereby pathological neovessels are targeted for regression while preserving the required normal vascular bed. Retinopathy is a two-phased disease initiated by vessel loss. The resulting hypoxia drives a pathologic response, neovascularization, which when unchecked can progress to blindness. Optimal therapy would eliminate neovascular growth while sparing normal vessels that are essential to tissue homeostasis. An attractive approach in this context considers innate immunity, mediated in part by the complement system. To date, the contribution of complement in proliferative retinopathy is poorly understood. Here we will characterize the role of the complement system in the formation and clearance of pathological neovessels in a mouse model of oxygen-induced retinopathy (OIR). We will determine the contribution of the classical, alternative and lectin complement pathways and endogenous membrane- bound complement inhibitors in vascular dropout, vessel regrowth after injury, neovessel development and neovessel regression during OIR progression. We will utilize knockout mice lacking each complement pathway and in mice containing only one functional complement pathway. Preliminary data demonstrates that the complement system plays an important role in eliminating neovessels while sparing normal vasculature. Complement factor-B, an activator of the alternative complement cascade, is significantly increased in retinas with neovascularization and is localized to neovessels. Mice lacking complement factor- B show increased severity and duration of neovascularization. Cd55, a complement inhibitor that protects healthy host cells from complement-associated destruction, is associated only with the normal vasculature and not neovessels. These data indicate that the alternative complement cascade is important in mediating the clearance of pathological neovessels in the retina. However the contributions of the other complement pathways in this process remain unknown. Understanding the mechanism by which the complement system mediates neovessel clearance may open new avenues of therapy for ROP and other blinding neovascular ophthalmic diseases.
In proliferative retinopathies, neovessels may regress, leaving only normal vessels;persistent neovessels can cause retinal cell death and progression to blindness. Emerging data implicate the complement system in host tissue repair and homeostasis during disease resolution. Elucidating the mechanism of endogenous neovessel regression while leaving the normal healthy vasculature untouched would be of great clinical interest.
|Hasegawa, Eiichi; Inafuku, Saori; Mulki, Lama et al. (2017) Cytochrome P450 monooxygenase lipid metabolites are significant second messengers in the resolution of choroidal neovascularization. Proc Natl Acad Sci U S A 114:E7545-E7553|
|Kim, Clifford B; D'Amore, Patricia A; Connor, Kip M (2016) Revisiting the mouse model of oxygen-induced retinopathy. Eye Brain 8:67-79|
|Kim, Clifford; Smith, Kaylee E; Castillejos, Alexandra et al. (2016) The alternative complement pathway aids in vascular regression during the early stages of a murine model of proliferative retinopathy. FASEB J 30:1300-5|
|Sampson, James F; Hasegawa, Eiichi; Mulki, Lama et al. (2015) Galectin-8 Ameliorates Murine Autoimmune Ocular Pathology and Promotes a Regulatory T Cell Response. PLoS One 10:e0130772|
|Sweigard, J Harry; Matsumoto, Hidetaka; Smith, Kaylee E et al. (2015) Inhibition of the alternative complement pathway preserves photoreceptors after retinal injury. Sci Transl Med 7:297ra116|
|Kataoka, K; Matsumoto, H; Kaneko, H et al. (2015) Macrophage- and RIP3-dependent inflammasome activation exacerbates retinal detachment-induced photoreceptor cell death. Cell Death Dis 6:e1731|
|Yanai, Ryoji; Mulki, Lama; Hasegawa, Eiichi et al. (2014) Cytochrome P450-generated metabolites derived from ?-3 fatty acids attenuate neovascularization. Proc Natl Acad Sci U S A 111:9603-8|
|Sweigard, J Harry; Yanai, Ryoji; Gaissert, Philipp et al. (2014) The alternative complement pathway regulates pathological angiogenesis in the retina. FASEB J 28:3171-82|
|Matsumoto, Hidetaka; Kataoka, Keiko; Tsoka, Pavlina et al. (2014) Strain difference in photoreceptor cell death after retinal detachment in mice. Invest Ophthalmol Vis Sci 55:4165-74|
|Mulki, Lama; Sweigard, J Harry; Connor, Kip M (2014) Assessing leukocyte-endothelial interactions under flow conditions in an ex vivo autoperfused microflow chamber assay. J Vis Exp :|
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