Wnt Signaling Mediates Pathological Vascular Growth in Proliferative Retinopathy

Abstract

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 oxygen-induced 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 down-regulation 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.

Pharmacologic Activation of Wnt Signaling by Lithium Normalizes Retinal Vasculature in a Murine Model of Familial Exudative Vitreoretinopathy

“…61 It is therefore critical to carefully titrate Wnt signaling and to promote it when it is deficient, as in this study with lithium treatment in Lrp5 À/À mice, whereas when Wnt signaling is abnormally up-regulated in other disease settings, it needs to be suppressed to the normal levels to prevent pathologic neovascularization. 11,12 This dual, opposing role of Wnt signaling is similar to the role of VEGF, which is essential for physiological vascular development and maintenance, and yet can be detrimental in pathologic conditions when up-regulated abnormally. In the absence of Wnt signaling in Lrp5 À/À retina, a compensatory VEGF elevation was observed, reflecting secondary hypoxia response in the lack of intralaminar vasculature, consistent with previous report of hypoxia-induced VEGF production in mice deficient of Norrin/Frizzled4 signaling.…”

“…After birth, retinal vessels in mice grow radially from the optic disk and reach peripheral retina by P7 to P8. 11,17 Lrp5 À/À mice displayed significantly less retinal vascular coverage and fewer branching points in the central superficial vascular plexus at P7 (Figure 1), compared with age-matched WT mice. Daily treatment with lithium (P1 to P7) accelerated retinal vascular growth, modestly improved superficial plexus vascular coverage (approximately 7.6% more than vehicle control), and substantially increased the number of branching points (approximately 42% more than vehicle control) at P7 compared with vehicle-treated Lrp5 À/À littermates (Figure 1), indicating a proangiogenic role of lithium in the development of superficial vascular plexus in Lrp5 À/À eyes.…”

“…8,12,15,16 In FEVR, lack of any one of LRP5/Frizzled4/TSPAN12/ Norrin causes deficient canonical Wnt signaling pathway at the ligand/receptor level, which allows the GSK3 complex to increase b-catenin degradation, resulting in eventual suppression of physiological vessel growth in the retina. 2,17 Both Sox17 and claudin5 were down-regulated in Wnt-deficient retinal vessels and were suggested to play a potential role in mediating vascular formation in FEVR retina, 11,18 although the exact underlying molecular mechanisms of Wnt signalingemediated retinal vascular defects are not completely understood yet. To date, there is no effective treatment for FEVR.…”

Endothelial microRNA-150 is an intrinsic suppressor of pathologic ocular neovascularization

“…All of these genes are potent proangiogenic genes associated with ocular angiogenesis. FZD4 is a receptor for Wnt signaling, which is a highly conserved angiogenic pathway activated in both OIR and laser-induced CNV models (16,33,34). On the other hand, Dll4/Notch signaling controls vessel sprouting and branching, and inhibition of DLL4 showed reduced pathological neovessels in OIR (35).…”

The Blood–Brain Barrier

“…b-Catenin also down-regulates the activity of Snail, which has a negative effect on the stability of p120/VE-cadherin complexes and on the expression of TJ molecules occludin and claudin-5. Loss of the Wnt coreceptor Lrp5 causes down-regulation of claudin-5 expression (Chen et al 2011). The Hh signaling pathway appears to drive the transcription and expression of junctional proteins, but also dampens inflammatory responses on CNS-ECs.…”