Conditional knockdown of tubedown-1 in endothelium results in neovascular retinopathy

Wall, Dana (2004) Conditional knockdown of tubedown-1 in endothelium results in neovascular retinopathy. Masters thesis, Memorial University of Newfoundland.

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Abstract

Abnormal blood vessel proliferation in the retina is the physical manifestation promoting blindness in neovascular retinopathies. Neovascular retinopathies include diabetic retinopathy, retinopathy of prematurity, and the 'wet form' of macular degeneration, and constitute the foremost cause of vision loss in developed nations. Uncontrolled angiogenesis is responsible for the aberrant neovascular phenotype. Vascular beds become chaotic and extend to form pre-retinal membranes covering the retinal tissue, and consequently structurally and functionally hinder vision. Elucidating the molecular biological events leading to the unregulated angiogenic surge will help in developing molecular treatments targeting the neovascular phenotype. Tubedown-1 (Thdn-1) is a novel protein expressed highly in adult ocular blood vessels. Tbdn-1 is homologous to the N-terminus of yeast Nat1 and co-purifies with an acetyltransferase activity. Previous data implicates Tbdn-1 as a negative regulatory modulator of capillary formation in adults. Furthermore, Thdn-1 protein expression is down-regulated in retinal blood vessels of patients with proliferative diabetic retinopathy compared to its high expression in normal retinal blood vessels. The objective of this thesis was to further investigate the role of Tbdn-1 in retinal vasculature by studying a mouse model enabling conditional knockdown of Tbdn-1 specifically in endothelial cells. Based on previous results, the hypothesis was suppression of Tbdn-1 in endothelium would result in an increase retinal angiogenesis. Histological analysis of retinas from mice demonstrating suppression of the Tbdn-1 protein revealed the presence of pre-retinal membranes coinciding with increased retinal neovascularization. The pre-retinal membranes also displayed the proliferation of glial cells and myofibrobasts, a decreased expression of basement membrane constituent heparan sulfate proteoglycan. Retinas exhibiting a prolonged down-regulation of Tbdn-1 showed an increase the size of pre-retinal membranes. Furthermore, the neovascular phenotype resulting from Tbdn-1 down-regulation appeared to be specific to the delicate retinal tissue, as it was not observed in other tissues. These results reinforce the hypothesis that Thdn-1 functions to dampen capillary formation in vivo. Loss of Tbdn-1 expression in the retina may alleviate a constraining force on endothelial cell remodeling allowing the outgrowth of endothelial cells to form neovascular networks.

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