Purchase this article with an account.
Eric Nudleman, Rajendra S. Apte; Activation of the Wnt Signaling Pathway in Neovascularization. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4828.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
In the human eye, the control of blood vessel formation (angiogenesis) is crucial,as the growth of abnormal blood vessels (neovascularization) leads to decreased vision and blindness in several diseases. Recent work has demonstrated a role for Wnt signaling in angiogenesis during development. However, a role for this pathway in pathological neovascularization remains unknown. Wnt7a and Wnt7b have been shown to be required for establishment of normal vasculature specific to the central nervous system. Inactivation of Wnt signaling in endothelial cells results in fragile vessels that are prone to fluid leakage and hemorrhage. Here we examine the hypothesis that Wnt signaling is also activated in pathologic choroidal and retinal neovascularization, which would provide a potential new target for the treatment of blinding diseases.
The Wnt signaling pathway was studied in choroidal neovascularization (CNV) in a well characterized laser injury induced murine model. Using mice expressing the BAT-GAL transgene, which expresses lacZ in cells where Wnt signaling is activated, CNV was induced by laser injury. Acivation of the Wnt pathway was then analyzed by confocal microscopy of choroidal flatmounts. Immunohistochemistry with antibodies against CD31 was used to stain the vasculature, and antibodies against B-galactosidase labeled cells where the Wnt pathway was activated. Similarly, the Wnt pathway was studied in oxygen induced retiniopathy (OIR), the murine model of retinopathy of prematurity (ROP). OIR was induced in the BAT-GAL animals, and retinal flatmounts were tested for the expression of lacZ in the proliferating retinal vessels. Finally, we tested the activity of the Wnt pathway in vitro by exposing microvascular endothlial cells to purified Wnt7a protein and testing for cellular proliferation.
Choroidal flatmounts of eyes with laser induced CNV showed specific activation of the Wnt signaling pathway in neovascular vessels. In addition, activation of the Wnt pathway in retinal neovascularization was demonstrated in mice exposed to OIR. Finally, purified Wnt7a protein was shown to induce proliferation in microvascular endothelial cells in vitro.
Here we demonstrate that the Wnt signaling pathway is activated in murine models of choroidal and retinal neovascualization. This work provides a foundation to further investigate the role of this pathway in neovasculazation and its potential as a therapeutic target.
This PDF is available to Subscribers Only