Angiogenesis Laboratory, Department of Ophthalmology, and.
Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, and.
FASEB J. 2014 Jul;28(7):3171-82. doi: 10.1096/fj.14-251041. Epub 2014 Mar 25.
A defining feature in proliferative retinopathies is the formation of pathological neovessels. In these diseases, the balance between neovessel formation and regression determines blindness, making the modulation of neovessel growth highly desirable. The role of the immune system in these retinopathies is of increasing interest, but it is not completely understood. We investigated the role of the alternative complement pathway during the formation and resolution of aberrant neovascularization. We used alternative complement pathway-deficient (Fb(-/-)) mice and age- and strain-matched control mice to assess neovessel development and regression in an oxygen-induced retinopathy (OIR) mouse model. In the control mice, we found increased transcription of Fb after OIR treatment. In the Fb(-/-) mice, we prepared retinal flatmounts and identified an increased number of neovessels, peaking at postnatal day 17 (P17; P=0.001). Subjecting human umbilical vein endothelial cells (HUVECs) to low oxygen, mimicking a characteristic of neovessels, decreased the expression of the complement inhibitor Cd55. Finally, using laser capture microdissection (LCM) to isolate the neovessels after OIR, we found decreased expression of Cd55 (P=0.005). Together, our data implicate the alternative complement pathway in facilitating neovessel clearance by down-regulating the complement inhibitor Cd55 specifically on neovessels, allowing for their targeted removal while leaving the established vasculature intact.-Sweigard, J. H., Yanai, R., Gaissert, P., Saint-Geniez, M., Kataoka, K., Thanos, A., Stahl, G. L., Lambris, J. D., Connor, K. M. The alternative complement pathway regulates pathological angiogenesis in the retina.
增生性视网膜病变的一个特征是病理性新生血管的形成。在这些疾病中，新生血管形成和消退的平衡决定了失明，因此高度需要调节新生血管的生长。免疫系统在这些视网膜病变中的作用越来越受到关注，但尚未完全了解。我们研究了补体替代途径在异常新生血管形成和消退中的作用。我们使用补体替代途径缺陷（Fb(-/-)）小鼠和年龄及品系匹配的对照小鼠来评估氧诱导的视网膜病变（OIR）小鼠模型中的新生血管发育和消退。在对照小鼠中，我们发现 OIR 治疗后 Fb 的转录增加。在 Fb(-/-)小鼠中，我们制备了视网膜平面，发现新生血管数量增加，在出生后第 17 天（P17；P=0.001）达到峰值。将人脐静脉内皮细胞（HUVEC）置于低氧环境中，模拟新生血管的特征，会降低补体抑制剂 Cd55 的表达。最后，使用激光捕获显微切割（LCM）在 OIR 后分离新生血管，我们发现 Cd55 的表达减少（P=0.005）。综上所述，我们的数据表明，补体替代途径通过下调新生血管上的补体抑制剂 Cd55 来促进新生血管清除，从而允许有针对性地去除新生血管，同时保持已建立的脉管系统完整。-Sweigard, J. H., Yanai, R., Gaissert, P., Saint-Geniez, M., Kataoka, K., Thanos, A., Stahl, G. L., Lambris, J. D., Connor, K. M. 补体替代途径调节视网膜中的病理性血管生成。
