Wnt Signaling Mediates Pathological Vascular Growth in Proliferative Retinopathy Clinical Perspective

Background—Ischemic proliferative retinopathy, characterized by pathologic retinal neovascularization, is a major cause of blindness in working age adults and children. Defining the molecular pathways distinguishing pathological neovascularization from normal vessels is critical to controlling these blinding diseases with targeted therapy. Because mutations in Wnt signaling cause defective retinal vasculature in humans with some characteristics of the pathologic vessels in retinopathy, we investigated the potential role of Wnt signaling in pathologic retinal vascular growth in proliferative retinopathy. Methods and Results—In this study we show that Wnt receptors (Frizzled4 and Lrp5) and activity are significantly increased in pathologic neovascularization in a mouse model of oxygeninduced proliferative retinopathy. Loss of Wnt co-receptor Lrp5 and downstream signaling molecule disheveled2 significantly decreases the formation of pathologic retinal neovascularization in retinopathy. Loss of Lrp5 also affects retinal angiogenesis during development and formation of the blood retinal barrier, which is linked to significant downregulation of tight junction protein claudin5 (Cln5) in Lrp5−/− vessels. Blocking Cln5 significantly suppresses Wnt-pathway driven endothelial cell sprouting in vitro and developmental and pathologic vascular growth in retinopathy in vivo. Conclusions—These results demonstrate an important role of Wnt signaling in pathologic vascular development in retinopathy and show a novel function of Cln5 in promoting angiogenesis. Correspondence should be addressed to: Lois E. H. Smith, M.D., Ph.D. Department of Ophthalmology, Harvard Medical School / Children’s Hospital Boston 300 Longwood Avenue, Boston MA 02115 Tel: 617 355 8531 [email protected]. Supplemental Data: Supplemental data include five figures and additional experimental procedures.