Abstract
Purpose: :
Macular Telangiectasia (MacTel) is a relatively rare disease of the eye, which causes progressive loss of central vision. The disease occurs in two phases, the first being non-proliferative in which there is loss of macular pigment, retinal capillary dilation and leakage. During the advanced stage the capillaries proliferate, become tortuous and invade the fovea. The MacTel project began in 2005, uniting labs with the aim of gaining insight into the causes and subsequent progression of Macular Telangiectasia.
Methods: :
Gene expression profiling was performed on retinal vessels isolated from three mutant mouse strains (Curlytail, VLDLR-/- and RD1) that display retinal vascular abnormalities similar to those in MacTel. Sixty-three genes were found to change in all three models. One gene which was significantly up-regulated was LBP (lipopolysaccharide binding protein). This is an acute-phase response glycoprotein, which through its binding to LPS and activation of TLR4 is involved in inflammatory signalling. LBP is a key protein in a regulatory switch in angiogenesis. In macrophages, the adenosine 2A receptor (A2AR) synergises with TLRs 2 and 4, preventing inflammatory signalling whilst inducing increased expression of vascular endothelial growth factor (VEGF) and promotion of neovascularisation.
Results: :
We are working to characterise the role of LBP in the retina and are testing the hypothesis that LBP is biologically active in the absence of LPS through as yet uncharacterised ligand(s). q-PCR analysis of VLDLR-/- mice has shown LBP to be expressed in the neuroretina, isolated vessels and RPE. We have collected data from P0-P96 mice and investigated the correlation between LBP, A2aR and VEGF expression. The progression of vascular remodelling and macrophage infiltration was studied in flat mounted retinas from P21-P96 animals. The effects of LBP on endothelial cell function in Matrigel and aortic ring assays indicate that LBP increases vessel sprouting in the absence of LPS. The ability of LBP to induce NFΚB activation has been investigated using a luciferase reporter assay and preliminary data suggest that LBP alone is capable of activating NFΚB.
Conclusions: :
In conclusion, we have revealed a potential role for LBP in contributing to retinal vascular remodelling in the absence of LPS. This work is funded by the MRC and Lowy Medical Research Institute.
Keywords: neovascularization • gene microarray • macula/fovea